Abstract
Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.
Highlights
IntroductionLATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells
Autophagy perturbation represents an emerging therapeutic strategy in cancer
While examining the role of the Hippo signaling pathway in the response of hepatocellular carcinoma (HCC) cells to Srf treatment, we discovered an unexpected cell survival role of LATS1
Summary
LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Autophagy deficiency promotes tumor initiation but represses malignant tumor progression and, as a consequence, autophagy plays a conflicting role in cancer therapy, including the treatment of HCC with Srf[6]. Acute treatment of HCC cells with Srf induces a lethal version of autophagy[7,8,9], a survival version of autophagy is likely to mediate the adaptive response to Srf and promotes cell viability in Srf-resistant cells[10,11]. The biological consequence of autophagy activation in response to therapy is context-dependent and the mechanistic understanding of how autophagy is regulated in cancer appears of great importance to optimize therapeutic interventions. Activated Hippo or MAP4Ks phosphorylate and activate the downstream kinases Large Tumor Suppressor 1 and 2
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