Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer [RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE253744 | GEO | 2024/05/09
REPOSITORIES: GEO
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Project description:To investigate the Nexturastat A effects on chromatin structure which disrupt phospho-HDAC6 LLPS in triple-negative breast cancer (TNBC), we conducted the analysis of Hi-C in TNBC cells treated with or without Nexturastat A.
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Project description:To further elucidate the role of phospho-HDAC6 LLPS in transcriptional regulation, we performed RNA-seq experiments in TNBC cells treated with Nexturastat A or HDAC6 knockdown
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Project description:Triple-negative breast cancer (TNBC) has a highly aggressive nature and distinct molecular characteristics from other subtypes of breast cancer and lacks effective targeted therapy. The molecular and genetic basis of cysteine/cystine dependency in TNBC is complex. We found that cysteine addiction associates with the expression of a set of Claudin genes in TNBC. The Claudin-high TNBCs are independent on cystine, while the Claudin-low TNBCs undergo rapid ferroptosis upon cystine deprivation or inhibition of cystine transport by erastin. To overcome the resistance of Claudin-high TNBC and luminal breast cancer to the potential targeted cystine-addiction therapy, we explored the synthetic lethality of cysteine by an epigenetic compound library screen. Several potent HDAC6 inhibitors were identified and rendered the Claudin-high TNBCs and luminal cancer cells dependent on extracellular cystine and undergoing ferroptosis upon cystine deprivation. The transcriptomic profiling showed that the HDAC6 inhibitor tubacin in combination with erastin activates a synthetic-lethal transcriptional program. Together, we have identified the HDAC6 inhibitors as potent therapy-sensitizers to revive the targeted cysteine-addiction therapy for various subtypes of breast cancer, not limit in the Claudin-low TNBC.
2021-06-02 | GSE154425 | GEO
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress
Project description:Foxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression and protein function. Pan-HDAC inhibitors developed for oncology enhance Treg production and suppression but have limited non-oncologic applications given their broad effects. We show, using HDAC6-deficient mice and WT mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully MHC-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein, HSP90. Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of HDAC6 knock out, compared to wild type (C57BL6) control
2011-05-01 | E-GEOD-27896 | biostudies-arrayexpress
Project description:Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin?s IDR, tandemly dispersed phenylalanine-and-glycine (FG) repeats. However, it remains elusive how unstructured IDRs contribute to oncogenesis. We show that IDR harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in leukemias, is essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukemic transformation. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TFs but is also required for formation of a broad, ?super-enhancer?-like binding pattern, typically seen at a battery of leukemogenic genes, potentiating their transcriptional activation. Artificial HOX chimera (FUS-HOXA9), created by replacing NUP98?s FG repeats with an unrelated LLPS-forming IDR of FUS, had similar enhancement effects on chimera?s genome-wide binding and target gene activation. Hi-C mapping further demonstrated that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin looping enriched at proto-oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish oncogenic TF condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As LLPS-competent molecules are frequently implicated in diseases, this mechanism can potentially be generalized to many malignant and pathological settings.
2021-04-19 | GSE144642 | GEO
Project description:Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin?s IDR, tandemly dispersed phenylalanine-and-glycine (FG) repeats. However, it remains elusive how unstructured IDRs contribute to oncogenesis. We show that IDR harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in leukemias, is essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukemic transformation. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TFs but is also required for formation of a broad, ?super-enhancer?-like binding pattern, typically seen at a battery of leukemogenic genes, potentiating their transcriptional activation. Artificial HOX chimera (FUS-HOXA9), created by replacing NUP98?s FG repeats with an unrelated LLPS-forming IDR of FUS, had similar enhancement effects on chimera?s genome-wide binding and target gene activation. Hi-C mapping further demonstrated that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin looping enriched at proto-oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish oncogenic TF condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As LLPS-competent molecules are frequently implicated in diseases, this mechanism can potentially be generalized to many malignant and pathological settings.
2021-04-19 | GSE144076 | GEO
Project description:Analysis of mouse ESCs overexpressing HDAC6. Histone deacetylase 6 (Hdac6) was discovered as a deacetylase of α-tubulin and functions in cell migration, immunity and resistance to virus infection in vitro. HDAC6 overexpression ESCs and control ESCs were selected for RNA extraction and hybridization on Agilent microarrays. Results provide insight into the role of HDAC6 in the mouse ESCs.
2016-12-01 | GSE81710 | GEO
Project description:To identify the functional role of Hdac6 in embryonic stem cells, we examined gene expression changes in mouse ES cells upon Tip60, Hdac6 and double knockdown. Two biological replicates each for control (GFP), Tip60, Hdac6 and double KD in E14 mouse ESCs. Lentiviral-based shRNA was used and gene expression changes were determined 3 days after KD. The global gene expression profiles of Tip60, Hdac6 and double KD were compared to control KD cells.
2013-11-20 | E-GEOD-42208 | biostudies-arrayexpress
Project description:ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most mutated epigenetic regulator in human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with ARID1A mutational status remain a challenge. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated ovarian tumors. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumors. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylated the Lysine 120 residue of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53’ apoptotic function by upregulating HDAC6. These results indicate that pharmacological inhibition of HDAC6 is a novel therapeutic strategy involving ARID1A-mutation
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