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YAP/TAZ and ATF4 collaboratively drive resistance to Sorafenib therapy in hepatocellular carcinoma by preventing ferroptosis

ABSTRACT: YAP/TAZ and ATF4 collaboratively drive resistance to Sorafenib therapy in hepatocellular carcinoma by preventing ferroptosis

PROVIDER: PRJNA753454 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15403056.fastq.gz	Fastqsanger.gz
	SRR15403057.fastq.gz	Fastqsanger.gz
	SRR15403058.fastq.gz	Fastqsanger.gz
	SRR15403059.fastq.gz	Fastqsanger.gz
	SRR15403060.fastq.gz	Fastqsanger.gz

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Similar Datasets

YAP/TAZ and ATF4 collaboratively drive resistance to Sorafenib therapy in hepatocellular carcinoma by preventing ferroptosis

Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis. Mechanistically, in a TEAD-dependent manner YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovered a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance.

2021-08-20 | GSE181771 | GEO

YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis

Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis. Mechanistically, in a TEAD-dependent manner YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance.

| S-SCDT-EMM-2021-14351 | biostudies-other

YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis.

Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis. Mechanistically, in a TEAD-dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance.

| S-EPMC8649869 | biostudies-literature

USP22 promotes the proliferation and inhibits Sorafenib-induced ferroptosis of hepatocellular carcinoma cells through its deubiquitinase activity

Project description:Hepatocellular carcinoma (HCC) remains one of the most lethal cancers, characterized by poor prognosis and low life expectancy. Unfortunately, there are very few molecular therapeutic options available for advanced HCC. Sorafenib is a current standard first-line treatment for advanced HCC, but drug resistance significantly limits its therapeutic efficacy. In this study, we identified ubiquitin-specific protease 22 (USP22) as the key regulator of HCC development and Sorafenib resistance. Analysis of TCGA databases revealed that USP22 is highly expressed in HCC tissues and is closely associated with poor patient prognosis. Our data further indicated that USP22 promotes the proliferation of HCC cells via deubiquitinating and stabilizing cyclin-dependent kinase 11B (CDK11B). Additionally, USP22 acts as a novel inducer of Sorafenib resistance and suppresses Sorafenib-triggered ferroptosis in HCC cells. It reduces the transcription of the transferrin receptor (TFRC) by decreasing H2BK120ub occupancy at TFRC transcription start site (TSS) downstream region, thereby inhibiting ferroptosis upon Sorafenib treatment. Finally, animal experiments confirmed the role of USP22 in promoting HCC cell growth and Sorafenib resistance in vivo. Taken together, our findings suggest that USP22 represents a promising prognostic biomarker and therapeutic target for HCC patients, particularly those with Sorafenib resistance.

2024-10-03 | GSE278684 | GEO

RNA seq data of sorafenib resistant HepG2 cells

Project description:To investigate the molecular mechanism of ferroptosis resistance in HCC, we applied sorafenib, one of the class I ferroptosis inducers (FINs), to generate HepG2 sorafenib resistant (SR) cells.

2024-02-03 | GSE248764 | GEO

USP22 promotes the proliferation and inhibits Sorafenib-induced ferroptosis of hepatocellular carcinoma cells through its deubiquitinase activity [ChIP-seq]

2024-10-03 | GSE278685 | GEO

Quantitative Time-Course Profiling of Sorafenib-Treated Hepatocellular Carcinoma (HCC) Cells Through Phosphoproteome Analysis

Project description:Ferroptosis is a new form of regulated, non-apoptotic cell death characterized by excessive lipid peroxidation upon loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). Sorafenib, an FDA-approved multi-kinase inhibitor drug for treatment of hepatocellular carcinoma (HCC), has been shown to induce ferroptosis. Protein phosphorylation changes upon Sorafenib treatment have been previously reported in patient studies and in cell culture however the early phosphorylation changes during induction of ferroptosis are not completely understood. This work highlights these changes through a time course from 7 to 60 min of Sorafenib treatment in SKHep1 cells to provide insight on the induction of ferroptosis. 6,186 unique phosphosites were quantified from 2,381 phosphoproteins in this study and phosphorylation changes occurred in as early as 30 minutes of Sorafenib treatment. By 60 minutes, significant changes in key regulatory pathways were identified, including sites from ferroptosis-related proteins, indicating the involvement of phospho-regulated signaling during ferroptosis induction.

2019-07-26 | MSV000084140 | MassIVE

A CRISPR/Cas9 library screening identified CARM1 as a critical inhibitor for Sorafenib-induced ferroptosis in hepatocellular carcinoma cells

Project description:CARM1 inhibits ferroptosis through promoting the transcription of GPX4. HepG2 cells expressing control shRNAs or CARM1 shRNAs were treated with Sorafenib for 24 hours, and then the mRNAs were extracted and subjected to RNA-seq.

2023-01-01 | GSE215263 | GEO

Expression profile of RCC4 cells with TAZ (WWTR1) silencing

Project description:TAZ, also known as WWTR1, is the one of the effectors of Hippo pathway. With its paralog, YAP, TAZ promotes organ size growth as well as tumor metastasis. In human renal carcinoma cells, we found that TAZ-silencing induces resisntance toward erastin-induced ferroptosis. In this study, TAZ is silencing in clear cell carcinoma cell line RCC4 to elucidate the downstream targets that promotes the resistance toward erastin-induced ferroptosis.

2019-09-03 | GSE121689 | GEO

Pioneering function of Yap and Taz in promoting osteogenesis of neural crest cells by preventing chondrogenesis

Project description:Neural crest cells (NCCs) are multipotent stem cells with a remarkable ability to differentiate into multiple cell lineages, including osteoblasts and chondrocytes. NCCs contribute to the majority of craniofacial skeleton, yet the molecular mechanisms regulating NCCs diversification into osteoblasts or chondrocytes remain poorly understood. We found that Yap and Taz function redundantly as key determinants of the osteogenesis versus chondrogenesis fate decision and differentiation in NCCs in vitro, ex vivo and in vivo, and Yap/Taz-deficiency in NCCs resulted in a switch from osteogenesis to chondrogenesis. Comprehensive analysis of unbiased datasets including CUT&RUN-seq and RNA-seq indicated that Yap/Taz directly regulate key genes that govern osteogenesis and chondrogenesis. During NCC-derived osteogenesis, Yap/Taz promote expression of osteogenic genes such as Runx2 and Sp7 but repress expression of chondrogenic genes such as Sox9 and Col2a1. Further, we found Yap/Taz directly interact with β-catenin in NCCs to coordinately promote osteoblast differentiation and repress chondrogenesis. Together our data indicate that Yap/Taz promote osteogenesis in NCCs by preventing chondrogenesis, partly through interactions with the Wnt-β-catenin pathway.

2022-11-02 | GSE154332 | GEO

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