Histone-acetyl Epigenome Regulates TGF-β Pathway-associated Chemoresistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA594405 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10612265.fastq.gz | Fastqsanger.gz | |||
| SRR10612266.fastq.gz | Fastqsanger.gz | |||
| SRR10612267.fastq.gz | Fastqsanger.gz | |||
| SRR10612268.fastq.gz | Fastqsanger.gz | |||
| SRR10612269.fastq.gz | Fastqsanger.gz |
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Project description:Histone-acetyl Epigenome Regulates TGF-β Pathway-associated Chemoresistance in Colorectal Cancer
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Project description:TGF-β signaling pathway has been demonstrated to be closely related to chemoresistance, which is the major cause of recurrence and poor outcome in colorectal cancer (CRC), however, the comprehensive epigenetic landscape that functionally implicates in the regulation of TGF-β pathway-associated chemoresistance has not yet well established in CRC. In our study, chromatin immunoprecipitation sequencing (ChIP-seq) and Western blot were employed to investigate epigenetic modifications for histones in response to TGF-β1 intervene. We found that the activation of the TGF-β pathway was characterized by genome-wide high levels of H3K9ac and H3K18ac. Mechanistically, the activation of the TGF-β signaling pathway leads to the downregulation of the deacetylase HDAC4, resulting in the upregulation of H3K9ac and H3K18ac. Consequently, this cascade induces oxaliplatin chemoresistance in CRC by triggering the anti-apoptotic PI3K/AKT signaling pathway. Our in vivo experiment results confirmed that overexpression of HDAC4 significantly enhances the sensitivity of CRC to oxaliplatin chemotherapy. Moreover, the expression level of HDAC4 was positively correlated with patients' prognosis in CRC. Our data suggest that histone-acetyl modification demonstrates a crucial role in modulating TGF-β pathway-associated chemoresistance in CRC, and HDAC4 would be a biomarker for prognostic prediction and potential therapeutic target for treatment in CRC.
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Project description:Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy–related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic events downstream of TGF-β signaling remain incompletely understood. Here, we identify hypoxic tumor microenvironment as an initiator of TGF-β signaling to promote HIF-2α positive CSC-mediated chemoresistance in high-grade serous ovarian cancer (HGSOC). Mechanistically, deubiquitinase USP9X, as a TGF-β downstream effector, stabilizes HIF-2ɑ in a hydroxylation- and ubiquitylation-dependent manner, thus promoting stemness reprogramming. Hypoxia and TGF-β signals converge on USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses. Clinically, USP9X expression correlates with TGF-β signatures, CSCs characteristics, EMT behaviors, and chemotherapy responsiveness, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increasing chemosensitivity in orthotopic tumors, patient derived xenograft (PDX), organoid, and chemoresistant cell models, in part via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in stimulating TGF-β signaling, and a downstream USP9X-HIF-2ɑ proteostatic regulatory axis in priming the HGSOC stemness, thereby provides novel targeting venues to counteract TGF-β signaling in CSCs and meliorate clinical chemoresistance.
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Project description:Widespread intraperitoneal metastases and chemoresistance has made ovarian cancer the leading cause of gynecological malignancy–related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. Whereas, how the signaling is activated and how to target TGF-β signaling precisely remain as key challenges. Here, we identify hypoxic tumor microenvironment as the initiator of TGF-β signaling so as to induce HIF-2α positive CSCs and chemoresistance in HGSOC. Mechanistically, deubiquitinase USP9X, as the TGF-β downstream effector, stabilizes HIF-2ɑ in hydroxylation and ubiquitylation dependent manner, thus activates stemness programming. Hypoxia and TGF-β signals promote USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses, thus coordinating the two pathways. Clinical USP9X is highly correlated with TGF-β signatures, CSCs characteristics, EMT behaviors, and stimulated by chemotherapies, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increases chemosensitivity, through orthotopic tumor, patient derived xenograft (PDX), organoid and chemoresistant cell models, via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in turning up TGF-β signaling, as well as USP9X-HIF-2ɑ proteostatic regulation in priming the HGSOC stemness, thus provides a promising strategy to counteract TGF-β signaling by targeting USP9X in CSCs and meliorate clinical chemoresistance.
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