Biology subjects

Xu, L.-Y.

Publications and source records attributed to Xu, L.-Y..

6 recordsLinked to original sources

bioRxiv2024

ANLN directly interacts with PCNA to regulate UV induced translesion synthesis

Anillin (ANLN) is a cytoskeletal binding protein involved in mitosis. ANLN is located in the nucleus during interphase and in the cytoplasmic contractile rings during mitosis. Our previous studies found that ANLN is abnormally overexpressed in esophageal squamous cell carcinoma (ESCC), promoting cell division by regulating contractile ring localization. However, the exact function of ANLN in the nucleus remains unclear. Here, we found that the expression of ANLN in the nucleus is associated with poor prognosis in ESCC patients, rather than in the cytoplasm. Protein mass spectrometry and bioinformatics analysis revealed that ANLN is related to DNA synthesis, and proliferating cell nuclear antigen (PCNA) is found to be a potential interacting protein of ANLN. PCNA directly interacts with the PIP box domain of ANLN and co-localizes in the nucleus. ANLN promotes DNA replication and S phase progression in a PCNA dependent manner and independent with the cytoskeletal function of ANLN. Importantly, ANLN is involved in transletion synthesis (TLS), a type of DNA synthesis under stress, by promoting PCNA monoubiquitination at K164 residue. Mechanistically, ANLN binds and recruits the E3 ligase RAD18 to promote PCNA monoubiquitination and DNA polymerase eta loading under UV radiation conditions. Consistently, depletion of ANLN leads to increased genomic instability and increased sensitivity to UV radiation. The findings of the study showed that ANLN in the nucleus as a protein scaffold is involved in UV induced DNA synthesis pathway, providing new insights into the function and mechanism of ANLN in cancer cells.

cancer biology↗

bioRxiv2023

CHAF1A promotes the translesion DNA synthesis pathway in response to DNA replication stress

The translesion DNA synthesis (TLS) pathway mediated by proliferating cell nuclear antigen (PCNA) monoubiquitination is an essential mechanism by which cancer cells bypass DNA damage caused by DNA replication stress to maintain genomic stability and cell survival. Chromatin assembly factor 1 subunit A (CHAF1A) traditionally promotes histone assembly during DNA replication. Here, we revealed that CHAF1A is a novel regulator of the TLS pathway. High expression of CHAF1A is significantly associated with poor prognosis in cancer patients. CHAF1A promotes fork restart under DNA replication stress and maintains genome integrity. CHAF1A enhances the interaction between PCNA and E3 ubiquitin protein ligase RAD18 and promotes PCNA monoubiquitination, thereby promoting the recruitment of Y-family DNA polymerase Pol {eta} and enhancing cancer cell resistance to stimuli that trigger replication fork blockade. Mechanistically, CHAF1A-mediated PCNA monoubiquitination is independent of CHAF1A-PCNA interaction. CHAF1A interacts with both RAD18 and replication protein A2 (RPA2), mediating RAD18 binding on chromatin in response to DNA replication stress. Taken together, these findings improve our understanding of the mechanisms that regulate the TLS pathway and provide insights into the relationship between CHAF1A and the malignant progression of cancers.

cell biology↗

bioRxiv2022

Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation

As one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), arising from distinct cells-of-origin. However, distinguishing cell-type-specific molecular features from cancer-specific characteristics has been challenging. Here, we analyze whole-genome bisulfite sequencing (WGBS) data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both the methylation level (depth) and genomic distribution (breadth) of PMDs across tumor samples. We identify subtype-specific PMDs, which are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While the genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie the genomic distribution PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor such as HNF4A can maintain the binding sites that it establishes in normal cells, while being recruited to new binding sites with novel partners such as FOSL1 in cancer. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of the cell-type-specific PMDs and DMRs identified here in esophageal cancer, are actually markers that co-occur in other cancers originating from related cell types. These findings advance our understanding of the DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.

cancer biology↗

bioRxiv2022

LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression

Lysyl-oxidase like-2 (LOXL2) regulates extracellular matrix remodeling and promotes tumor invasion and metastasis. Altered metabolism is a core hallmark of cancer, however, it remains unclear whether and how LOXL2 contributes to tumor metabolism. Here, we found that LOXL2 and its catalytically inactive L2{Delta}13 splice variant also function as novel deacetylases that trigger metabolic reprogramming during malignant transformation. Integrated transcriptomic and metabolomic analysis revealed that L2{Delta}13-overexpressing transgenic mice displayed perturbed glucose and lipid metabolism, which was associated with increased hepatic fibrosis and enhanced formation of precancerous lesions induced by chemical carcinogens, such as carbon tetrachloride and N-nitrosomethylbenzylamine. Furthermore, both LOXL2 and L2{Delta}13 boosted glucose metabolism of esophageal tumor cells, thereby facilitating tumor cell proliferation in vitro and in vivo. Mechanistically, LOXL2 and L2{Delta}13 interacted physically with several glycolic proteins including aldolase A to enhance their enzymatic activities and mobilization from the actin cytoskeleton. Using SILAC followed by proteomic analysis, we identified LOXL2 as a deacetylase targeting metabolic proteins in esophageal cancer. Importantly, both LOXL2 and L2{Delta}13 directly catalyzed the deacetylation of aldolase A at K13, resulting in enhanced glycolysis which subsequently reprogramed tumor metabolism and promoted tumor progression. High level expression of LOXL2/L2{Delta}13 combined with decreased acetylation of aldolase-K13 predicted poor clinical outcome in patients with esophageal cancer. In summary, we have characterized a novel molecular mechanism that mediates the pro-tumorigenic activity of LOXL2 independently of its classical amine oxidase activity. These findings may enable the future development of therapeutic agents targeting the metabolic machinery via LOXL2 or L2{Delta}13.

cell biology↗

bioRxiv2021

Characterization of epigenetic alterations in esophageal cancer by whole-genome bisulfite sequencing

Esophageal carcinoma is a common and aggressive malignancy, and its patients have dismal clinical outcomes. The epigenetic dysregulation in both major subtypes, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), awaits further characterization. Here, we perform whole-genome bisulfite sequencing (WGBS) on a total of 43 esophageal cancer and normal samples, generating one of the largest WGBS datasets in this cancer to date. Focusing on hypomethylated regions in cancer, we show that they are associated with increased chromatin activity and enhancer RNA expression. Using this large collection of WGBS dataset, we reveal and validate novel clusters in both ESCC and EAC. We further identify specific molecular features in each cluster, with potential clinical implications. These data together advance our understanding of the epigenetic alterations in esophageal cancer and provide a rich resource for the research community of this disease.

cancer biology↗

bioRxiv2019

Lineage-Specific Epigenomic and Genomic Activation of the Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

BackgroundsGastrointestinal adenocarcinomas (GIACs) of the tubular GI tract including esophagus, stomach, colon and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIACs are less well-characterized.We applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks using 907 GIAC samples from The Cancer Genome Atlas (TCGA). Complementary epigenomic technologies were performed to investigate HNF4A activation, including Circularized Chromosome Conformation Capture (4C), Chromatin immunoprecipitation (ChIP) sequencing, Whole Genome Bisulfite Sequencing (WGBS), and Assay for Transposase-Accessible Chromatin (ATAC) sequencing. In vitro and in vivo cellular phenotypical assays were conducted to study HNF4A functions.\n\nResultsWe identified a list of functionally hyperactive master regulator (MR)TFs shared across different GIACs. As the top candidate, HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. We further characterized a complex interplay between HNF4A promoter and three distal enhancer elements, which was coordinated by GIAC-specific MRTFs including ELF3, GATA4, GATA6 and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptionally activating many downstream targets including HNF1A and factors of Interleukin signaling in a lineage-specific manner.\n\nConclusionWe use a large cohort of patient samples and an unbiased mathematical approach to highlight lineage-specific oncogenic MRTFs, which provide new insights into the GIAC-specific gene regulatory networks, and identify potential therapeutic strategies against these common cancers.

cancer biology↗