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 2

STRIPAK-MST1/2 undergoes dynamic assembly in response to DNA damage.

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STRIPAK-MST1/2 undergoes dynamic assembly in response to DNA damage. (A ...
(A and B) Gels showing DNA damage–triggered stabilization of the SIKE1-SLMAP arm at the protein level. Here, 293A cells were pretreated with the indicated dose of etoposide (A) or with other DNA-damaging agents (B) for 1 hour, and then harvested 2 hours after removal of the chemicals. (C–E) Gels and plots showing a DNA damage–induced mutually exclusive pattern between SIKE1-SLMAP protein levels and MST1/2 kinase activity. Cells were exposed to 10 μM etoposide for 1 hour and then collected at the indicated time points after removal of the drug to determine the (C) protein levels of both SIKE1 and SLMAP in 293A cells and (D) MST1/2 kinase activity in HGC-27 cells. (E) Quantitative data from HGC-27 cells. (F) Dynamic assembly of STRIPAK-MST1/2 induced by DNA damage. 293A cells transiently transfected with the indicated constructs for 24 hours were treated with DMSO or etoposide (1 h) and then harvested at an early (2 h) or late (18 h) stage before being subjected to BioID analysis. (G) Co-IP assay to validate the BioID results. 293A cells were treated and harvested as in C before processing for STRN3 IP. (H) Cartoon representation of a loosening of the assembly of the Hippo-containing STRIPAK complex in response to DNA damage. See also Supplemental Figure 3.