Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis
Seung-Hyun Ro,
Xiang Xue,
Sadeesh K Ramakrishnan,
Chun-Seok Cho,
Sim Namkoong,
Insook Jang,
Ian A Semple,
Allison Ho,
Hwan-Woo Park,
Yatrik M Shah,
Jun Hee Lee
Affiliations
Seung-Hyun Ro
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States; Department of Biochemistry, University of Nebraska, Lincoln, United States
Xiang Xue
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Sadeesh K Ramakrishnan
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Chun-Seok Cho
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Sim Namkoong
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Insook Jang
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Ian A Semple
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Allison Ho
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Hwan-Woo Park
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States; Department of Cell Biology, College of Medicine, Konyang University, Daejeon, Republic of Korea; Myung-Gok Eye Research Institute, Konyang University, Seoul, Republic of Korea
Yatrik M Shah
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53’s control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis.
