Sel1L-Hrd1 ER-Associated Degradation Suppresses Hepatocyte Hyperproliferation and Liver Cancer

Endoplasmic reticulum (ER) homeostasis has been implicated in the pathogenesis of various forms of cancer; however, our understanding of the role of ER quality-control mechanisms in tumorigenesis remains greatly limited. Here, we show that the Sel1L-Hrd1 complex of ER-associated degradation (ERAD) suppresses hepatocyte proliferation and tumorigenesis in mice. Hepatocyte-specific deletion of <i>Sel1L</i> or <i>Hrd1</i> predisposed mice to diet/chemical-induced tumors, with hyperproliferative hepatocytes. Proteomics screen of microsomes from Sel1L -deficient livers revealed Wnt5A, a tumor suppressor, as an ERAD substrate. Indeed, nascent Wnt5A was misfolding prone and degraded by Sel1L-Hrd1 ERAD. In the absence of ERAD, Wnt5A was largely retained in the ER and formed high molecular-weight aggregates, thereby potentially attenuating Wnt5A-mediated suppression of hepatocyte proliferation. In humans, SEL1L-HRD1 ERAD expression correlated positively with survival time for liver cancer patients, and was elevated in liver tumors. Overall, our data reveal a key role of Sel1L-Hrd1 ERAD in suppressing hepatocyte proliferation and liver cancer.