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?Np73 enhances HIF-1? protein stability through repression of the ECV complex.

ABSTRACT: Cellular responses to low oxygen conditions are mainly regulated by the Hypoxia-inducible factors (HIFs). Induction of HIF-1? in tumor cells activates the angiogenic switch and allows for metabolic adaptations. HIF-1? protein levels are tightly regulated through ubiquitin-mediated proteosomal degradation; however, high levels of HIF-1? is a common feature in many solid tumors and is thought to enhance cancer cell proliferation, migration, and survival. Here, we report that the oncogenic p73 isoform, ?Np73, increases HIF-1? protein stability. We found that ?Np73 represses expression of genes encoding subunits of the ECV complex, in particular Elongin C, Elongin B, Cullin 2, and Rbx1. The ECV complex is an E3 ligase complex responsible for polyubiquitinating HIF-1?. Loss of ?Np73 increases ubiquitination of HIF-1?, leading to its degradation via the proteosomal pathway, and subsequent decrease of HIF-1? target genes. Taken together, our data demonstrates that high levels of ?Np73 stabilize HIF-1? protein, allowing for it to accumulate and further potentiating its transcriptional activity and supporting tumor progression.

SUBMITTER: Stantic M

PROVIDER: S-EPMC6033838 | biostudies-other | 2018 Jul

REPOSITORIES: biostudies-other

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ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex.

Stantic Marina M Wolfsberger Johanna J Sakil Habib A M HAM Wilhelm Margareta T MT

Oncogene 20180409 27

Cellular responses to low oxygen conditions are mainly regulated by the Hypoxia-inducible factors (HIFs). Induction of HIF-1α in tumor cells activates the angiogenic switch and allows for metabolic adaptations. HIF-1α protein levels are tightly regulated through ubiquitin-mediated proteosomal degradation; however, high levels of HIF-1α is a common feature in many solid tumors and is thought to enhance cancer cell proliferation, migration, and survival. Here, we report that the oncogenic p73 isof ...[more]

PMID: 29628507

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Project description:Background: Previous studies have shown that EZH2 regulates tumor PD-L1 expression at the transcriptional level and has an impact on tumor immune environment and prognosis. However, whether EZH2 can regulate PD-L1 expression at the post-translational level remains unclear. Therefore, this study aims to investigate the effects of EZH2 inhibition on PD-L1 expression and protein stability in colorectal cancer cells, uncover its underlying mechanisms, and provide new therapeutic strategies for anti-tumor immune therapy. Methods: Multiple colorectal cancer cell models were used to examine the effects of EZH2 inhibition on PD-L1 expression and protein stability at both the protein and transcriptional levels. Transcriptome analysis was performed to identify differentially expressed genes associated with EZH2 inhibition and potential effectors involved in EZH2-mediated regulation of PD-L1 protein stability. Validation of candidate genes was conducted through public database analysis and knockdown or overexpression models. Finally, the combined effects of EZH2 inhibitors and anti-PD-1 immune therapy were evaluated using a mouse xenograft model. Results: We observed that inhibition of EZH2 function upregulated PD-L1 expression and enhanced its protein stability in colorectal cancer cells. Transcriptome analysis revealed that ubiquitin-specific protease 22 (USP22) played a crucial role in mediating EZH2-regulated PD-L1 protein stability. EZH2 affected USP22 expression through its classical epigenetic regulatory function, thereby modulating PD-L1 expression stability and influencing the tumor immune microenvironment. Combination treatment with EZH2 inhibitors and anti-PD-1 immune therapy improved the tumor microenvironment, promoted immune cell infiltration, and exerted synergistic anti-cancer effects. Conclusion: This study elucidated the mechanisms by EZH2 regulate PD-L1 expression and stability, providing new insights into therapeutic strategies for colorectal cancer. The combination of EZH2 inhibitors and anti-PD-1 immune therapy can synergistically enhance anti-tumor effects. These findings offer a potential therapeutic approach to improve the effectiveness of EZH2 inhibitors in cancer treatment and contribute to a better understanding of the role of EZH2 in tumor immune regulation.

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?Np73 enhances HIF-1? protein stability through repression of the ECV complex.

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ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex.

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