Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers
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
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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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 7

Loss of Hippo kinase activity endows cancer cells with resistance to radio- and chemotherapy.

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Loss of Hippo kinase activity endows cancer cells with resistance to rad...
(A) Plot showing that MST1/2 ablation restored HR repair in STRIPAK component–deficient cells. 293A cells (WT or KOs) were transfected with the indicated siRNAs before being subjected to an HR reporter assay (n = 3). (B) Images of samples from HGC-27 cells (WT and SIKE1/SLMAP-DKO) transfected with the indicated siRNAs and then subjected to a sphere formation assay (n = 3). Scale bar: 60 μm. (C–F) Results showing that MST2 deficiency induced radioresistance in vivo. (C) WT and Stk3–/– mice were exposed to 6 Gy whole-body IR. Residual DNA damage in intestinal tissues was examined at 3 days via both (D) Western blotting and (E) immunofluorescence analysis using anti–γ-H2AX antibody, and (F) overall survival was assessed until 6 weeks after IR. Representative images in intestinal tissues were quantified and analyzed (n = 8 glands from 2 mice in each group). Scale bar: 10 μm. (G) Images showing that MST1/2 inactivation promoted cancer cell resistance to etoposide. HGC-27 cells were treated with etoposide with or without XMU–MP-1 and analyzed using the sphere formation assay (n = 3). Scale bar: 60 μm. (H) Reduced MST1/2 kinase activity in tumor tissues after chemotherapy. IHC analysis of p-MST1/2 staining of tissues derived from adjacent normal tissue, GC tumors, and GC tumors after oxaliplatin treatment. Scale bar:100 μm, the enlarged inserts were magnified 5 times form original images. (I) Schematic illustration of the negative correlation between Hippo kinase activity and acquired drug resistance. **P < 0.01 and ***P < 0.001, by unpaired Student’s t test (A and E) and 1-way ANOVA with Dunnett’s post hoc test (B and G). The survival analysis was performed using the log-rank test (F). See also Supplemental Figure 8.