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Journal of Clinical Investigation

Journal of Clinical Investigation

IF: 13.3
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PP2A inhibition causes synthetic lethality in BRCA2 -mutated prostate cancer models via spindle assembly checkpoint reactivation

Published:2 January 2024 DOI: 10.1172/JCI172137 PMID: 37934606
Jian Wang,?Yuke Chen,?Shiwei Li,?Wanchang Liu,?Xiao Albert Zhou,?Yefei Luo,?Zhanzhan Xu,?Yundong Xiong,?Kaiqi Cheng,?Mingjian Ruan,?Wei Yu,?Xiaoman Li,?Weibin Wang,?Jiadong Wang

Abstract

Mutations in the BRCA2 tumor suppressor gene have been associated with an increased risk of developing prostate cancer. One of the paradoxes concerning BRCA2 is the fact that its inactivation affects genetic stability and is deleterious for cellular and organismal survival, while BRCA2-mutated cancer cells adapt to this detriment and malignantly proliferate. Therapeutic strategies for tumors arising from BRCA2 mutations may be discovered by understanding these adaptive mechanisms. In this study, we conducted forward genetic synthetic viability screenings in Caenorhabditis elegans brc-2 (Cebrc-2) mutants and found that Ceubxn-2 inactivation rescued the viability of Cebrc-2 mutants. Moreover, loss of NSFL1C, the mammalian ortholog of CeUBXN-2, suppressed the spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation. SAC inactivation is common in BRCA2-deficient prostate cancer patients, but PP2A inhibitors could reactivate the SAC and achieve BRCA2-deficient prostate tumor synthetic lethality. Our research reveals the survival adaptation mechanism of BRCA2-deficient prostate tumor cells and provides different angles for exploring synthetic lethal inhibitors in addition to targeting DNA damage repair pathways.

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