SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer

Asmita Bhattacharya; Juncheng Wei; Wenxin Song; Beixue Gao; Chunyan Tian; Shuangcheng Alivia Wu; Jian Wang; Ligong Chen; Deyu Fang; Ling Qi

doi:10.1016/j.isci.2022.105183

SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer

iScience. 2022 Sep 24;25(10):105183. doi: 10.1016/j.isci.2022.105183. eCollection 2022 Oct 21.

Authors

Asmita Bhattacharya^{1

2}, Juncheng Wei³, Wenxin Song⁴, Beixue Gao³, Chunyan Tian⁵, Shuangcheng Alivia Wu¹, Jian Wang⁵, Ligong Chen⁴, Deyu Fang³, Ling Qi^{1

6}

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
² Graduate Program of Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853, USA.
³ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China.
⁵ State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102206, China.
⁶ Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA.

Abstract

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 incomplete. Here, we show that the SEL1L-HRD1 complex of ER-associated degradation (ERAD) suppresses hepatocyte proliferation and tumorigenesis in mice. Hepatocyte-specific deletion of Sel1L or Hrd1 predisposed mice to diet/chemical-induced tumors. Proteomics screen 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 a quality control capacity. In the absence of ERAD, WNT5A misfolds is largely retained in the ER and forms high-molecular weight aggregates, thereby depicting a loss-of-function effect and attenuating WNT5A-mediated suppression of hepatocyte proliferation. In humans, SEL1L-HRD1 ERAD expression correlated positively with survival time for patients with liver cancer. Overall, our data reveal a key role of SEL1L-HRD1 ERAD in suppressing hepatocyte proliferation and liver cancer.

Keywords: Cancer; Cell biology; Molecular biology.