2. Academic Validation
  3. Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling

Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling

  • Oncogene. 2020 Apr;39(16):3336-3353. doi: 10.1038/s41388-020-1219-2.
Minghui Zhuo  # 1,  Wenbo Chen  # 2,  Shaohui Shang 1,  Peng Guo 1,  Kesong Peng 1 3,  Ming Li 4,  Pingli Mo 1,  Yongyou Zhang 1,  Xingfeng Qiu 5,  Wengang Li 6,  Chundong Yu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.
  • 2 Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 3 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 4 Department of Hepatobiliary and Pancreatic & Organ Transplantation Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 5 Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, China. dr.qxf@xmu.edu.cn.
  • 6 Department of Hepatobiliary and Pancreatic & Organ Transplantation Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. lwg11861@163.com.
  • 7 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China. cdyu@xmu.edu.cn.
  • # Contributed equally.
PMID: 32094404 DOI: 10.1038/s41388-020-1219-2
Abstract

Histone Demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal Cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog Inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis.

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