What is it about?

Ovarian cancer is one of the most common cancers and the deadliest gynecologic cancer globally, yet the molecular mechanism underlying ovarian cancer initiation and development remains unclear. Here, we show that DNA methylation-mediated epigenetic silence of deubiquitinase OTUB2 enhances ubiquitination and degradation of its substrate SNX29P2. SNX29P2 functions as a linker protein that promotes the E3 ligase VHL-mediated degradation of HIF-1α. OTUB2 silencing increases HIF-1α protein level and drives ovarian cancer initiation and chemoresistance via activation of its downstream target CA9. Remarkably, inhibition of CA9 exhibits promising efficacy in suppressing ovarian cancer models with silenced OTUB2, either alone or in combination with conventional chemotherapy.

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Why is it important?

Our study highlights the pivotal role of OTUB2/SNX29P2 in suppressing ovarian cancer development and proposes that targeting CA9-mediated glycolysis is an encouraging strategy for the treatment of ovarian cancer.


OTUB2 has been previously reported to function as an oncoprotein in several cancer types, including breast cancer, lung cancer, gastric cancer, and colorectal cancer. However, our recent study demonstrated a tumor-suppressive role for OTUB2 in tongue and esophageal squamous cell carcinomas. In the current study, we identified ovarian cancer as another cancer type that can be driven by OTUB2 silencing.

Zhihua Liu
China Academy of Chinese Medical Sciences

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This page is a summary of: OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition, Proceedings of the National Academy of Sciences, May 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2315348121.
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