Biology subjects

Meng, X.

Publications and source records attributed to Meng, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

O-GlcNAcylation of Keratin 18 coordinates TCA cycle to promote cholangiocarcinoma progression

Glycosylation in human cholangiocarcinoma (CCA) actively contributes to pathophysiological steps of tumor progression. Of note is the dynamic modification of proteins by O-linked {beta}-N-acetyl-glucosamine (O-GlcNAcylation) that modulates various tumor-associated biological activities. By using a cutting-edge chemical proteomic methodology for intact glycopeptide analysis, we show herein that O-GlcNAcylation of Keratin 18 (K18) coordinates the tricarboxylic acid (TCA) cycle enzymes, namely isocitrate dehydrogenases (IDHs), to promote CCA progression. Mechanistically, site-specific O-GlcNAcylation of K18 on Ser 30 stabilizes K18, which benefits the expression of cell cycle checkpoints to enhance cell cycle progression and cell growth. Interaction with IDHs down-regulates the level of citrate and isocitrate, while up-regulates the level of -ketoglutarate (-KG). Our study thus expands the current understanding of protein O-GlcNAcylation, and adds another dimension of complexity to post-translational control over metabolism and tumorigenesis.

cancer biology↗

bioRxiv2023

Palmitoylation of the Hemagglutinin of Influenza B virus by ER-localized DHHC enzymes 1, 2, 4 and 6 is essential for virus replication

Covalent attachment of the fatty acids palmitate or stearate to the cytoplasmic domain of viral glycoproteins is often crucial for viral replication. This has previously been studied for the hemagglutinin (HA) of Influenza A virus and the responsible enzymes have been identified, but similar studies have not been performed with HA of Influenza B virus, which contains palmitate linked to two cysteines. We show here that the modification is essential for virus replication since exchange of both cysteines or the cysteine located at the end of the cytoplasmic tail prevented the generation of viable viruses. Viruses with an exchange of the membrane-distal cysteine rapidly reverted back to wild-type virus. Blocking exit of proteins from the endoplasmic reticulum (ER) revealed that palmitoylation of HA of Influenza B virus occurs in the ER, whereas acylation of HA of Influenza A virus also in the Golgi. Infecting cells deficient in DHHC palmitoyltransferases revealed that HA of Influenza B virus is acylated by the ER-localized DHHCs 1, 2, 4 and 6, which are thus different from the enzymes previously identified for acylation of HA of Influenza A virus. A comparison of predicted and experimentally determined protein structures suggests that the exclusive acylation of the HA of Influenza B virus with palmitate is not a function of the responsible DHHCs and that the transmembrane region may be critical for the acylation of HA of Influenza A and B virus by different DHHCs. ImportanceInfluenza viruses are a public health concern since they cause seasonal outbreaks and occasionally pandemics. Our study investigates the importance of a protein modification called "palmitoylation" in the replication of Influenza B virus. Palmitoylation involves attaching fatty acids to the viral protein hemagglutinin, and has previously been studied for Influenza A virus. We found that this modification is essential for the Influenza B virus to replicate, as mutating the sites where palmitate is attached prevented the virus from generating viable particles. Our experiments also showed that this modification occurs in the endoplasmic reticulum. We identified the specific enzymes responsible for this modification, which are different from those involved in palmitoylation of HA of Influenza A virus. Overall, our research illuminates the similarities and differences in fatty acid attachment to HA of Influenza A and B virus and identifies the responsible enzymes, which might be promising targets for antiviral therapy.

cell biology↗

bioRxiv2023

High-resolution structure of mouse radial spoke and its in-situ structure in ependymal cilia revealed by cryo-EM and cryo-ET

Radial spokes (RS) transmit mechanochemical signals between the central pair (CP) and axonemal dynein arms to coordinate ciliary motility. However, the high-resolution structure of mammalian RS remains missing. Here, we present the high-resolution cryo-EM structure of mouse RS head-neck complex in both monomer and dimer forms and reveal the intrinsic dynamics of the dimer. We also map the genetic mutations related to primary ciliary dyskinesia and asthenospermia on the head-neck complex. Moreover, we present the unprecedented cryo-ET and sub-tomogram averaging map of mouse ependymal cilia, whose beating creates unidirectional cerebrospinal fluid flow, and build the models for RS1-3, IDAs, and N-DRC. Strikingly, our cryo-ET map reveals the lack of IDA-b/c/e and the absence of tektin filaments within the A-tubule of doublet microtubules in ependymal cilia compared with mammalian respiratory cilia and sperm flagella. This tissue-specific feature may represent an evolutionary choice driven by the functional requirements on ependymal cilia. Our findings reveal the RS head-neck assembly mechanism, shed light on the coordinated rigid and elastic RS-CP interaction modes beneficial for the regulation of asymmetric ciliary beating, and also facilitate understandings on the etiology of ciliary dyskinesia-related ciliopathies.

biophysics↗

bioRxiv2023

Gene prediction and evolutionary characterization of heat shock transcription factors in Salvia miltiorrhiza

BackgroundHeat shock transcription factors (HSFs) serve as central regulators in plants and enable adaptations to dynamic environmental changes, such as heat stress. Salvia miltiorrhiza is an important medicinal plant model. However, various biotic and abiotic stresses, pathogen infections, and degeneration of elite cultivars limit the yield and quality of S. miltiorrhiza. Therefore, it is important to predict and characterize the stress resistance genes of S. miltiorrhiza and clarify potential molecular mechanisms for genetic improvement. However, the knowledge of HSF genes in S. miltiorrhiza is limited. MethodsThus, we performed a genome-wide analysis of HSF genes in S. miltiorrhiza. ResultsUsing high-quality genome sequences, we predicted 34 HSF genes distributed unevenly across eight chromosomes. Twenty-three genes were segmentally duplicated, suggesting that in S. miltiorrhiza, segmental duplications have significantly contributed to the expansion of the HSF gene family. The predicted genes were divided into 15 phylogenetic groups, among which the sequence characteristics were relatively well conserved. The Ka/Ks ratios indicated that duplicated HSF genes underwent negative selection. Most of the HSF genes displayed different expression characteristics under drought stress and salicylic acid induction. This study provides valuable data that may inform further functional studies of HSF genes in S. miltiorrhiza.

bioinformatics↗

bioRxiv2023

Microsporidia dressing up: the spore polaroplast transport through the polar tube and transformation into the sporoplasm membrane

Microsporidia are obligate intracellular parasites that infect a wide variety of hosts, including humans. Microsporidian spores possess a unique, highly specialized invasion apparatus involving the polar filament, polaroplast and posterior vacuole. During spore germination, the polar filament is discharged out of the spore forming the hollow polar tube that transports the sporoplasm components including nucleus into the host cell to achieve the invasion. Due to the complicated topological changes occurring in this process, the formation of sporoplasm is unclear. Here, electron microscopy observation and DiI staining confirmed that during spore germination, a large number of vesicles derived from the polaroplast, nucleus and other cytoplasm were transported out via the polar tube. Meanwhile, the posterior vacuole and plasma membrane remained in the empty spore coat. In addition, there was no DiI-labeled membrane around the nucleus in mature spores, whereas a DiI-labeled limit membrane wrapping nucleus was found at the tip of the extruded polar tube, suggesting that the membrane of sporoplasm was formed outside the mature spore. Two Nosema bombycis sporoplasm surface proteins (NbTMP1 and NoboABCG1.1) were located at the polaroplast in mature spores, in the extruded polar tube and on the sporoplasm membrane, which indicated that the polaroplast transported via the polar tube finally became the limiting membrane of the sporoplasm. Golgi-tracker green and Golgi marker protein syntaxin 6 were also found the same model, which was consistent with the transported polaroplast derived from Golgi transformed into the novel sporoplasm membrane during spore germination. ImportanceMicrosporidia, obligate intracellular pathogenic organisms, cause huge economic losses in agriculture and even threaten human health. The key to successful infection of microsporidia is its unique invasion apparatus which includes the polar filament, polaroplast and posterior vacuole. When the spore is activated to geminate, the polar filament uncoils and undergoes a rapid transition into the hollow polar tube that will transport the sporoplasm components including nucleus into a host cell to achieve the invasion. Knowledge of structure difference between polar filament and polar tube, the process of cargo transport in extruded polar tube, and the formation of the sporoplasm membrane are still poorly understood. Herein, we verify that the polar filament evaginates to form the polar tube, which serves as a conduit for transporting elongated nucleus and other sporoplasm components. And we confirm that the transported polaroplast finally transforms into the novel sporoplasm membrane during spore germination. Our study provides new insights into the cargo transportation process of polar tube and origin of the sporoplasm membrane, which serve as foundations for clarifying the microsporidian infection mechanism.

pathology↗

bioRxiv2023

Rare SH2B3 coding variants identified in lupus patients impair B cell tolerance and predispose to autoimmunity

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3 - a negative regulator of cytokine and growth factor receptor signaling - harbors rare coding variants in over 5% of SLE patients. Here we show that unlike the variant found exclusively in healthy controls, most SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles. Generation of two mouse lines carrying variants orthologous to those found in patients revealed SH2B3 is important to limit the numbers of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk. SummaryZhang et al. reveal a role for hypomorphic SH2B3 in lupus risk. The study shows rare and damaging variants identified in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.

immunology↗

bioRxiv2023

Plant Arbovirus Mobilizes a Vector Salivary Protein to Initiate Plant Infection

Plant viruses typically rely on insect vectors for transmission between plants, with insect salivary proteins playing critical roles in this process. In this study, we demonstrate how Laodelphax striatellus salivary carbonic anhydrase (LssaCA) promotes rice stripe virus (RSV) infection in plants. We discovered that LssaCA directly binds to RSV nucleocapsid protein (NP) in insect salivary glands. This LssaCA-NP complex interacts with a rice thaumatin-like protein (OsTLP) that possess endo-{beta}-1,3-glucanase activity potentially degrading callose. Upon binding, the LssaCA-NP complex significantly enhances OsTLP enzymatic activity. We further clarify that both L. striatellus feeding and RSV infection induce callose deposition. The tripartite LssaCA-NP-OsTLP interaction enhances callose degradation, thereby facilitating RSV infection via its insect vector. This study provides new insights into complex virus-insect-plant tripartite interactions mediated by insect salivary proteins, with broad implications for numerous plant viruses transmitted by insect vectors.

plant biology↗

bioRxiv2023

Expanding the family of genetically encoded voltage indicators: Insights from heliorhodopsins

Genetically encoded voltage indicators (GEVIs), particularly those based on microbial rhodopsins, are gaining traction in neuroscience as fluorescent sensors for imaging voltage dynamics with high-spatiotemporal precision. Here we establish a novel GEVI candidate based on the recently discovered subfamily of the microbial rhodopsin clade, termed heliorhodopsins. We discovered that upon excitation at 530-560nm, wild type heliorhodopsin exhibits near infra-red fluorescence which is sensitive to membrane voltage. We characterized the fluorescence brightness, photostability, voltage sensitivity and kinetics of wild type heliorhodopsin in HEK293T cells and further examined the impact of mutating key residues near the retinal chromophore. The S237A mutation significantly improved the fluorescence response of heliorhodopsin by 76% providing a highly promising starting point for further protein evolution.

biophysics↗

bioRxiv2023

Distance-dependent reconfiguration of hubs in Alzheimer's disease:a cross-tissue functional network study

The hubs of the intra-grey matter (GM) network were sensitive to anatomical distance and susceptible to neuropathological damage. However, few studies examined the hubs of cross-tissue distance-dependent networks and their changes in Alzheimers disease (AD). Using resting-state fMRI data of 30 AD patients and 37 normal older adults (NC), we constructed the cross-tissue networks based on functional connectivity (FC) between GM and white matter (WM) voxels. In the full-ranged and distance-dependent networks (characterized by gradually increased Euclidean distances between GM and WM voxels), their hubs were identified with weight degree metrics (frWD and ddWD). We compared these WD metrics between AD and NC; using the resultant abnormal WDs as the seeds, we performed seed-based FC analysis. With increasing distance, the GM hubs of distance-dependent networks moved from the medial to lateral cortices, and the WM hubs spread from the projection fibers to longitudinal fascicles. Abnormal ddWD metrics in AD were primarily located in the hubs of distance-dependent networks around 20-100mm. Decreased ddWDs were located in the left corona radiation (CR), which had decreased FCs with the executive networks GM regions in AD. Increased ddWDs were located in the posterior thalamic radiation (PTR) and the temporal-parietal-occipital junction (TPO), and their FCs were larger in AD. Increased ddWDs were shown in the sagittal striatum, which had larger FCs with the salience networks GM regions in AD. The reconfiguration of cross-tissue distance-dependent networks possibly reflected the disruption in the neural circuit of executive function and the compensatory changes in the neural circuits of visuospatial and social-emotional functions in AD.

neuroscience↗

bioRxiv2023

Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway

Abnormalities in crosstalk between the thalamus and the cerebral cortex are thought to lead to severe neuropsychiatric disorders, such as epilepsy and psychotic disorders. Pathogenic variants in the CACNA1G gene, which encodes the 1G subunit of the thalamus-enriched T-type voltage-gated calcium channel CaV3.1, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit level consequences of these genetic variants in humans remain unknown. Here, we developed an in vitro human assembloid model of the thalamocortical pathway to systematically dissect the contribution of genetic variants in T-type calcium channels. We discovered that a CACNA1G variant (M1531V) associated with seizures led to changes in T-type currents in human thalamic neurons, as well as correlated hyperactivity of thalamic and cortical neurons in thalamo-cortical assembloids. In contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to both increased spontaneous thalamic activity and aberrant thalamic axonal projections. Taken together, these results illustrate the utility of organoid and assembloid systems for interrogating human genetic disease risk variants at both cellular and circuit level.

neuroscience↗

bioRxiv2023

Mitochondrial metabolism in primary and metastatic human kidney cancers

Most kidney cancers display evidence of metabolic dysfunction1-4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse 13C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-13C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2-13C]acetate and [U-13C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.

cancer biology↗

bioRxiv2022

An oral vaccine for SARS-CoV-2 RBD mRNA-bovine milk-derived exosomes induces a neutralizing antibody response in vivo

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has presented numerous challenges to global health. The vaccines, including lipid-based nanoparticle mRNA, inactivated virus and recombined protein, have been used to prevent SARS-CoV-2 infections in clinics and are immensely helpful against the epidemic. Here, we first present an oral mRNA vaccine based on bovine milk-derived exosomes (milk-exos), which encodes the SARS-CoV-2 receptor binding domain (RBD) as an immunogen. The results indicated that RBD mRNA delivered by milk-derived exosomes can produce secreted RBD peptide in 293 cells in vitro and stimulated neutralizing antibodies against RBD in mice. These results indicated that bovine milk-derived exosome-based mRNA vaccine could serve as a new strategy for preventing SARS-CoV-2 infection. Meanwhile, it also can work as a new oral delivery system for mRNA. One Sentence SummaryOral SARS-CoV-2 mRNA vaccine based on bovine milk-derived exosomes can stimulate neutralizing antibodies in mice.

immunology↗

bioRxiv2022

Developmentally programmed switches in DNA replication: gene amplification and genome-wide endoreplication in Tetrahymena.

Locus-specific gene amplification and genome-wide endoreplication generate the elevated copy number of ribosomal DNA (rDNA, 9000 C) and non-rDNA (45 C) chromosomes in the developing macronucleus of Tetrahymena thermophila. Subsequently, all macronuclear chromosomes replicate once per cell cycle during vegetative growth. Here we describe an unanticipated, programmed switch in the regulation of replication initiation in the rDNA minichomosome. Early in development the 21 kb rDNA minichromosome is preferentially amplified from 2 C to ~800 C from well-defined origins, concurrent with genome-wide endoreplication (2 C to 8-16 C) in starved mating Tetrahymena (endoreplication (ER) Phase 1). Upon refeeding, rDNA and non-rDNA chromosomes achieve their final copy number through resumption of just the endoreplication program (ER Phase 2). Unconventional rDNA replication intermediates are generated primarily during ER phase 2, consistent with delocalized replication initiation and possible formation of persistent RNA-DNA hybrids. Origin usage and replication fork elongation are affected in non-rDNA chromosomes as well. Despite the developmentally programmed 10-fold reduction in the ubiquitous eukaryotic initiator, the Origin Recognition Complex (ORC), active initiation sites are more closely spaced in ER phases 1 and 2 compared to vegetative growing cells. We propose that initiation site selection is relaxed in endoreplicating macronuclear chromosomes and may be less dependent on ORC.

molecular biology↗

bioRxiv2022

Three-dimensional molecular architecture of mouse organogenesis

Mammalian embryos have sophisticated cell organizations that are orchestrated by molecular regulation at cellular and tissue level. It has recently been appreciated that the cells that make up the animal body themselves harbor significant heterogeneity in the context of both cellular and particularly spatial dimension. However, current spatial transcriptomics profiling of embryonic tissues either lack three-dimensional representation or are restricted to limited depth and organs. Here, we reported a holistic spatial transcriptome atlas of all major organs at embryonic day 13.5 of mouse embryo and delineated a 3D rendering of the molecular regulation of embryonic patterning. By integrating with corresponding single-cell transcriptome data, the spatial organogenesis atlas provides rich molecular annotation of the dynamic organ nature, spatial cellular interaction, embryonic axes and divergence of cell fates underlying mammalian development, which would pave the way for precise organ-engineering and stem-cell based regenerative medicine.

developmental biology↗

bioRxiv2022

Allele-specific gene editing approach for vision loss restoration in RHO-associated Retinitis Pigmentosa

Mutant RHO is the most frequent genetic cause of autosomal dominant retinitis pigmentosa. Here, we developed an allele-specific gene editing therapeutic drug to selectively target the human T17M RHO mutant allele while leaving the wild-type RHO allele intact for the first time. We identified a Staphylococcus aureus Cas9 (SaCas9) guide RNA that was highly active and specific to the human T17M RHO allele. In vitro experiments using HEK293T cells and patient-specific induced pluripotent stem cells (iPSCs) demonstrated active nuclease activity and high specificity. Subretinal delivery of a single adeno-associated virus serotype 2/8 packaging SaCas9 and sgRNA to the retinas of the RHO humanized mice showed that this therapeutic drug targeted the mutant allele selectively, thereby downregulating the mutant RHO mRNA expression. Administration of this therapeutic drug resulted in a long-term (up to 11 months after treatment) improvement of retinal function and preservation of photoreceptors in the mutant humanized heterozygous mice. Our study demonstrated a dose-dependent therapeutic effect in vivo. Unwanted off-target effects were not observed at the whole-genome sequencing level. Our study provides strong support for the further development of this effective therapeutic drug to treat RHO-T17M associated autosomal dominant retinitis pigmentosa (adRP), also offers a generalizable framework for developing gene editing medicine. Furthermore, our success in retoring the vision loss in the suffering RHO humanized mice verifies the feasibility of allele-specific CRISPR/Cas9-based medicines for other autosomal dominant inherited retinal dystrophies.

genetics↗

bioRxiv2022

Multi-model order spatially constrained ICA reveals highly replicable group differences and consistent predictive results from fMRI data

Brain functional networks identified from resting fMRI data have the potential to reveal biomarkers for brain disorders, but studies of complex mental illnesses such as schizophrenia (SZ) often yield mixed results across replication studies. This is likely due in part to the complexity of the disorder, the short data acquisition time, and the limited ability of the approaches for brain imaging data mining. Therefore, the use of analytic approaches which can both capture individual variability while offering comparability across analyses is highly preferred. Fully blind data-driven approaches such as independent component analysis (ICA) are hard to compare across studies, and approaches that use fixed atlas-based regions can have limited sensitivity to individual sensitivity. By contrast, spatially constrained ICA (scICA) provides a hybrid, fully automated solution that can incorporate spatial network priors while also adapting to new subjects. However, scICA has thus far only been used with a single spatial scale. In this work, we present an approach using scICA to extract subject-specific intrinsic connectivity networks (ICNs) from fMRI data at multiple spatial scales (ICA model orders), which also enables us to study interactions across spatial scales. We evaluate this approach using a large N (N>1,600) study of schizophrenia divided into separate validation and replication sets. A multi-scale ICN template was estimated and labeled, then used as input into spatially constrained ICA which was computed on an individual subject level. We then performed a subsequent analysis of multiscale functional network connectivity (msFNC) to evaluate the patient data, including group differences and classification. Results showed highly consistent group differences in msFNC in regions including cerebellum, thalamus, and motor/auditory networks. Importantly, multiple msFNC pairs linking different spatial scales were implicated. We also used the msFNC features as input to a classification model in cross-validated hold-out data and also in an independent test data. Visualization of predictive features was performed by evaluating their feature weights. Finally, we evaluated the relationship of the identified patterns to positive symptoms and found consistent results across datasets. The results verified the robustness of our framework in evaluating brain functional connectivity of schizophrenia at multiple spatial scales, implicated consistent and replicable brain networks, and highlighted a promising approach for leveraging resting fMRI data for brain biomarker development.

neuroscience↗

bioRxiv2022

CRISPR screens in 3D assembloids reveal disease genes associated with human interneuron development

The assembly of cortical circuits involves the generation and migration of cortical interneurons from the ventral to the dorsal forebrain, which has been challenging to study in humans as these processes take place at inaccessible stages of late gestation and early postnatal development. Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development, but which of the hundreds of NDD genes impact interneuron generation and migration into circuits and how they mediate these effects remain unknown. We previously developed a stem cell-based platform to study human cortical interneurons in self-organizing organoids resembling the ventral forebrain and their migration using forebrain assembloids. Here, we integrate assembloid technology with CRISPR screening to systematically investigate the involvement of 425 NDD genes in human interneuron development. The first screen aimed at interneuron generation revealed 13 candidate genes, including the RNA-binding protein CSDE1 and the canonical TGF{beta} signaling activator SMAD4. Then, we ran an interneuron migration screen in [~]1,000 forebrain assembloids that identified 33 candidate genes, including cytoskeleton-related genes and, notably, the endoplasmic reticulum (ER)-related gene LNPK. Interestingly, we discovered that, during interneuron migration, the ER is displaced along the leading neuronal branch prior to nuclear translocation. Deletion of LNPK interfered with this ER displacement and resulted in reduced interneuron saltation length, indicating a critical role for the ER in this migratory process. Taken together, these results highlight how this versatile CRISPR-assembloid platform can be used to systematically map disease genes onto early stages of human neural development and to reveal novel mechanisms regulating interneuron development.

neuroscience↗

bioRxiv2022

Sirt3 enhanced Bufalin sensitivity of colorectal cancer cells through P53-dependent pathway of apoptosis Sirt3 enhanced Bufalin sensitivity of colorectal cancer cells through P53-dependent pathway of apoptosis

Sirt3, one of class III histone deacetylase, is mainly localized in mitochondria and plays a significant role in the control of the metabolic activity, senescence and death [1]. Recently, Sirt3 emerged as a novel member of anticancer. However, the role of Sirt3 in colorectal cancer (CRC) has never been explained exactly. In this study, we found that sirt3 is down-regulated after Bufalin treatment. We also found that AC-P53 is up-regulated which induces Bax translocation to mitochondrion and open the mitochondrial permeability transition (mPTP) pores result in the release of cytochrome C lead to the activation of caspase-dependent apoptosis pathway. Collectively, our data suggests that Sirt3 may play an important role in CRC development and progression and may be a promising therapeutic target for CRC.

cancer biology↗