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DPP9 Stabilizes NRF2 to Suppress Ferroptosis and Induce Sorafenib Resistance in Clear Cell Renal Cell Carcinoma

ABSTRACT: DPP9 Stabilizes NRF2 to Suppress Ferroptosis and Induce Sorafenib Resistance in Clear Cell Renal Cell Carcinoma

PROVIDER: PRJNA1013351 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25917745_1.fastq.gz	Fastqsanger.gz
	SRR25917745_2.fastq.gz	Fastqsanger.gz
	SRR25917746_1.fastq.gz	Fastqsanger.gz
	SRR25917746_2.fastq.gz	Fastqsanger.gz
	SRR25917747_1.fastq.gz	Fastqsanger.gz

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DPP9 Stabilizes NRF2 to Suppress Ferroptosis and Induce Sorafenib Resistance in Clear Cell Renal Cell Carcinoma

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Project description:Here, through genome-wide CRISPR-Cas9 screenings, we identified GAS41, a well-known histone reader as a major repressor for ferroptosis. GAS41 interacts with NRF2 and is critical for NRF2 to activate its targets such as SLC7A11 for modulating ferroptosis. By recognizing the H3K27-acetylation (H3K27-ac) marker, GAS41 is recruited to the SLC7A11 promoter independent of NRF2 binding. Notably, by bridging the interaction between NRF2 and the H3K27-ac marker, GAS41 acts as an anchor for NRF2 on chromatin in a promoter-specific manner for transcriptional activation. Moreover, the GAS41-mediated effect on ferroptosis contributes significantly to its oncogenic role in vivo. These data demonstrate that GAS41 is an important target for modulating tumor growth through ferroptosis. Our study reveals a previously unanticipated mechanism for GAS41-mediated regulation in transcription by anchoring NRF2 on chromatin and provides a model that the DNA binding activity on chromatin by transcriptional factors (NRF2) can be directly regulated by histone markers (H3K27-ac).

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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.

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Project description:Earlier studies linked sorafenib effectiveness to induction of ferroptosis. Herein we demonstrate sorafenib and mTKIs downregulate DDX5 in vitro and in vivo. To understand the effect of DDX5 downregulation, we compared TCGA-derived HCCs expressing low vs. high DDX5 focusing on ferroptosis-related genes. Glutathione Peroxidase 4 (GPX4), a key ferroptosis regulator, was significantly overexpressed in DDX5LOW HCCs. Importantly, DDX5-knockdown (DDX5KD) HCC cell lines lacked lipid peroxidation by GPX4 inhibition, indicating DDX5 downregulation suppresses ferroptosis. RNAseq analyses comparing wild type vs. DDX5KD cells in the presence or absence of sorafenib, identified a unique set of genes repressed by DDX5 and upregulated by sorafenib. This set significantly overlaps genes from Wnt/β-catenin and non-canonical NF-κB pathways, including NF-κB inducing Kinase required for non-canonical NF-κB activation. Pharmacologic inhibition of these pathways in combination with sorafenib reduced DDX5KD cell viability. Mechanistically, sorafenib-mediated NF-κB activation induced NRF2 transcription, while DDX5KD extended NRF2 half/life by stabilizing p62/SQSTM1, leading to enhanced expression of GPX4 and ferroptosis escape. Conclusion: Sorafenib/mTKI-mediated DDX5 downregulation results in adaptive mTKI resistance by enhancing NRF2 expression, leading to ferroptosis escape. We propose inhibition of the pathways leading to NRF2 expression will enhance the therapeutic effectiveness of sorafenib/mTKIs.

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