Biology subjects

Seto, E.

Publications and source records attributed to Seto, E..

5 recordsLinked to original sources

bioRxiv2023

HDAC10 blockade upregulates SPARC expression thereby repressing melanoma cell growth and BRAF inhibitor resistance

Secreted Protein Acidic and Rich in Cysteine (SPARC), a highly conserved secreted glycoprotein, is crucial for various bioprocesses. Here we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression. HDAC10 depletion or inhibition upregulates, while overexpression of HDAC10 downregulates, SPARC expression. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the acetylation state of histone H3 lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth, primarily by induction of autophagy via activation of AMPK signaling. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitivity of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through epigenetic modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC. HighlightsO_LIHDAC10 is the primary HDAC member that tightly controls SPARC expression. C_LIO_LIHDAC10 coordinates with p300 in modulating the H3K27ac state at SPARC regulatory elements and the recruitment of BRD4 to these regions. C_LIO_LIHDAC10 depletion and resultant SPARC upregulation inhibit melanoma cell growth by inducing autophagy via activation of AMPK signaling. C_LIO_LISPARC upregulation as a result of HDAC10 depletion resensitizes resistant cells to BRAF inhibitors. C_LI

cancer biology↗

bioRxiv2022

HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a neural crest stem cell (NCSC)-like transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a NCSC gene expression signature and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. scRNA-seq analyses showed that HDAC8 expression was correlated with the NCSC cell state in clinical MBM specimens. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion and resistance to stress. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development.

cancer biology↗

bioRxiv2018

HDAC11 Deficiency Prevents High-Fat Diet-Induced Obesity and Metabolic Syndrome

Significance StatementObesity is a serious and widespread health problem which has become a growing concern in many societies. Most currently available weight-loss medications do not work for everyone, and the effects decline over time. Thus, there is an urgent need to identify new molecular targets to improve drug development for the treatment of obesity and obesity-related diseases. In this study, we discovered that the histone deacetylase 11 (HDAC11) enzyme is a key regulator of metabolism and obesity, and the absence of HDAC11 prevents obesity in mice. Our findings will facilitate the development of novel therapeutics to treat obesity by targeting HDAC11.\n\nAbstractObesity and its associated metabolic syndromes are the consequence of susceptible genes and obesogenic environments. We report here that histone deacetylase 11 (HDAC11) plays a critical role in the development of obesity and in metabolic homeostasis. HDAC11 knockout mice display resistance to high-fat diet-induced obesity and associated syndromes by enhancing glucose tolerance and insulin sensitivity, attenuating hypercholesterolemia and hyperinsulinemia, and blocking hepatosteatosis and liver damage. Mechanistically, HDAC11 deficiency boosts energy expenditure through promoting thermogenic capacity, which attributes to the elevation of uncoupling protein 1 (UCP1) expression and activity in brown adipose tissue. Moreover, loss of HDAC11 stimulates mitochondrial oxidation, elevates plasma adiponectin, and activates the adiponectin-AdipoR-AMPK pathway in the liver, which may contribute to a reversal in hepatosteatosis. These findings establish HDAC11 as a key regulator of metabolism and indicate that HDAC11 inhibitors may hold promise for treating overweight and obesity-related diseases.

molecular biology↗

bioRxiv2018

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to {beta}-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.

molecular biology↗

bioRxiv2017

HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2

The smallest histone deacetylase (HDAC) and the only class IV HDAC member, HDAC11, is reported to regulate immune activation and tumorigenesis, yet its physiological function is largely unknown. Here we identify HDAC11 as an efficient lysine defatty-acylase that is >10,000-fold more efficient than its deacetylase activity. Through proteomics studies, we identified SHMT2 as a defatty-acylation substrate of HDAC11. HDAC11-catalyzed defatty-acylation did not affect the enzymatic activity of SHMT2. Instead, it affects the ability of SHMT2 to regulate type I interferon receptor ubiquitination and internalization. Correspondingly, HDAC11 depletion increased type I interferon signaling in both cell culture and mice. This study is the first time a zinc-dependent HDAC is found to have an activity that is much more efficient than the corresponding deacetylase activity. The finding expands the physiological functions of HDAC11 and protein lysine fatty acylation, and opens up opportunities to develop HDAC11-specific inhibitors as therapeutics to modulate immune responses.

biochemistry↗