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The Hippo pathway kinase LATS1 scaffolds Beclin1 in autophagy regulation in hepatocellular carcinoma

ABSTRACT: Autophagy perturbation represents an emerging therapeutic strategy in cancer. The mammalian Hippo pathway is an evolutionary conserved tumor suppressive network, where the kinases LATS1/2 phosphorylate and inactivate oncogenic YAP/TAZ. Here, we demonstrated a pro-survival role of LATS1, but not LATS2, in hepatocellular carcinoma cells in response to sorafenib, a standard care of advanced HCC. Transcriptomic analysis revealed a restrictive role of LATS1 in autophagy regulation in HCC cells. Further, we found that the autophagy regulation by LATS1 was independent of its kinase activity. Instead, LATS1 stabilized autophagy core-machinery component Beclin 1 via promoting a non-canonical form of K27-linked ubiquitination, and consequently, inactive Beclin 1 self-dimer, in a E3 ligase NEDD4 dependent manner. Our study highlights a functional diversity between LATS1 and LATS2 and uncovers a scaffolding role of LATS1 in mediating a cross-talk between Hippo signalling and autophagy in HCC and therapy response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117116 | GEO | 2019/11/13

REPOSITORIES: GEO

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Expression profiling in primary embryonic fibroblasts deficient for the N-terminal truncation of Lats1

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The Hippo pathway kinase LATS1 scaffolds Beclin1 in autophagy regulation in hepatocellular carcinoma

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