Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers
Liwei An, … , Shi Jiao, Zhaocai Zhou
Liwei An, … , Shi Jiao, Zhaocai Zhou
Published March 15, 2022
Citation Information: J Clin Invest. 2022;132(9):e155468. https://doi.org/10.1172/JCI155468.
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Research Article Cell biology Gastroenterology

Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers

Abstract

The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type–containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1–induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1– sarcolemma membrane–associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.

Authors

Liwei An, Zhifa Cao, Pingping Nie, Hui Zhang, Zhenzhu Tong, Fan Chen, Yang Tang, Yi Han, Wenjia Wang, Zhangting Zhao, Qingya Zhao, Yuqin Yang, Yuanzhi Xu, Gemin Fang, Lei Shi, Huixiong Xu, Haiqing Ma, Shi Jiao, Zhaocai Zhou

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Figure 5

MST1/2 kinases suppress DSB repair in the nucleus.

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MST1/2 kinases suppress DSB repair in the nucleus. (A) Gels showing that...
(A) Gels showing that DNA damage enhanced nuclear localization of MST1/2 kinases. Samples of 293A cells treated with or without etoposide were subjected to the respective cell fractionation assays. (B and C) Schematic presentation of MST1 constructs (WT and mutants) (B) and their subcellular localization patterns (C). Scale bar: 10 μm. (D and E) Plot and gel showing that MST1 inhibited DSB repair in a manner dependent on its nuclear localization. 293A cells (WT and MST1-KO and its derivatives) were subjected to either (D, n = 3) a HR reporter assay or (E) Western blot analysis of γ-H2AX levels in HGC-27 MST1-KO cells expressing the indicated MST1 mutation 12 hours after IR treatment. (F and G) Schematic presentation of MST2 constructs (WT and mutants) (F) and their subcellular localization (G). Scale bar: 10 μm. (H and I) Plot and gel showing that MST2 inhibited DSB repair in a manner dependent on its nuclear localization. (H, n = 3) 293A MST2-KO cells and (I) HGC-27 MST2-KO cells were treated and processed as in D and E. *P < 0.05, ***P < 0.001, and ****P < 0.0001, by unpaired Student’s t test (D and H). See also Supplemental Figures 5 and 6.