Tumor suppressive role of Sestrin2 during colitis and colon carcinogenesis

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Abstract

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 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.

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Seung-Hyun Ro

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Xiang Xue

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Sadeesh K Ramakrishnan

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Chun-Seok Cho

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Sim Namkoong

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Insook Jang

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Ian A Semple

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Allison Ho

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Hwan-Woo Park

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Yatrik M Shah

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Jun Hee Lee

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States

For correspondence
leeju@umich.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal studies were ethically approved (protocol approval numbers: PRO00005712 and PRO00004019) and overseen by the University Committee on Use and Care of Animals (UCUCA) at the University of Michigan.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.