PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation
Jian Wang, … , Weibin Wang, Jiadong Wang
Jian Wang, … , Weibin Wang, Jiadong Wang
Published November 7, 2023
Citation Information: J Clin Invest. 2024;134(1):e172137. https://doi.org/10.1172/JCI172137.
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Research Article Cell biology Oncology

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

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.

Authors

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

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Figure 6

Inhibition of PP2A could reactivate the SAC in BRCA2-deficient cells.

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Inhibition of PP2A could reactivate the SAC in BRCA2-deficient cells. (A...
(A) mRNA levels of AURKB were assessed in samples from high-BRCA2-expression and low-BRCA2-expression prostate adenocarcinoma (PRAD) patients in the Memorial Sloan-Kettering Cancer Center (MSKCC) Prostate Oncogenome Project data set (from cBioPortal). Patients were separated into high BRCA2/AURKB or low BRCA2/AURKB on the basis of the 40th percentile of BRCA2/AURKB mRNA expression z scores. (B) Difference in disease-free survival between low- and all-BRCA2-expression PRAD patients in the MSKCC Prostate Oncogenome Project data set. Patients were separated into high BRCA2/AURKB or low BRCA2/AURKB on the basis of the 40th percentile of BRCA2/AURKB mRNA expression z scores. (C and D) Immunohistochemical staining of NSFL1C/AURKB was performed on tissue samples from PRAD patients with BRCA2 WT (n = 22) and BRCA2 mutant (n = 10). Left: Quantification of the expression degree of NSFL1C/AURKB, which was determined by the log-changed value of integral optical density. Right: Representative images. Insets show one enlargement of the outlined regions. Scale bars: 50 μm. (E) AURKBi (barasertib, 10 nM) restabilized cold-stable microtubules in BRCA2-deficient LNCaP cells. The frequency of K-fiber defects is shown (n = 3). See Supplemental Figure 6C for representative images of cold-stable microtubules. (F) PP2Ai (LB100, 10 μM) restored the AURKB-T232ph intensity in BRCA2/NSFL1C double-deficient LNCaP cells (n = 3), which is the direct marker of AURKB activity. See Supplemental Figure 6E for representative images. (G) PP2Ai (LB100, 10 μM) destroyed cold-stable microtubules in BRCA2/NSFL1C double-deficient LNCaP cells. The frequency of K-fiber defects is shown (n = 3). See Supplemental Figure 6F for representative images of cold-stable microtubules. Data indicate the mean ± SEM. *P < 0.05 and ****P < 0.0001. Unpaired, 2-tailed Student’s t test was used in A and C–E. The log-rank test was used in B. Two-way ANOVA was used in F and G.