TY - JOUR
T1 - SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer
AU - Bhattacharya, Asmita
AU - Wei, Juncheng
AU - Song, Wenxin
AU - Gao, Beixue
AU - Tian, Chunyan
AU - Wu, Shuangcheng Alivia
AU - Wang, Jian
AU - Chen, Ligong
AU - Fang, Deyu
AU - Qi, Ling
N1 - Funding Information:
We sincerely thank Dr. Dafydd Thomas for sharing tissue biopsies from human liver cancer patients; Dr. Richard Wojcikiewicz for reagents; Erik Peterson and Megan Schaller for technical assistance; and Drs. Robert Weiss, Peter Arvan, Natasza Kurpios and Kenneth Simpson for discussion and insightful comments; the Histology, Pathology, Vision, Animal testing and Vector Cores at the University of Michigan Medical School for assistance; Dr. Venkatesha Basrur and the Proteomics Core at the University of Michigan for proteomics analysis; and other members of the Qi laboratory for critique, discussion, and support. This work was supported by Ministry of Science and Technology of the People's Republic of China National Key R&D Programs 2018YFA0506903 (L.C.), American Diabetes Association 1-19-IBS-235 (L.Q.) and NIH 1R01DK120330 (L.Q. and D.F.). A.B. was in part supported by AHA Predoctoral Fellowship #16PRE29750001 .
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/10/21
Y1 - 2022/10/21
N2 - 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.
AB - 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.
KW - Cancer
KW - Cell biology
KW - Molecular biology
UR - http://www.scopus.com/inward/record.url?scp=85139311286&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139311286&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.105183
DO - 10.1016/j.isci.2022.105183
M3 - Article
C2 - 36238898
AN - SCOPUS:85139311286
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 10
M1 - 105183
ER -
