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


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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Fig. 1: JMJD2D expression is induced by TNFα and JMJD2D−/− mice are more sensitive to DSS-induced colitis compared with wild-type mice.
Fig. 2: JMJD2D protects colonic epithelial cells from DSS-induced apoptosis and promotes colonic epithelial cell proliferation by activating Hedgehog signaling.
Fig. 3: JMJD2D promotes CRC cell proliferation, xenograft growth, migration, invasion, and lung metastasis by activating Hedgehog signaling.
Fig. 4: JMJD2D promotes Hedgehog target gene transcription through interacting with Gli2 to reduce H3K9me3 levels at the promoter.
Fig. 5: JMJD2D and Gli2 are frequently overexpressed in human IBD and CRC specimens.
Fig. 6: 5-c-8HQ synergizes with vismodegib to reduce Hedgehog target gene expression and to inhibit CRC cell proliferation and tumorigenesis.
Fig. 7: Aspirin synergizes with Hedgehog inhibitor vismodegib to reduce Hedgehog target gene expression and to inhibit HCT116 cell proliferation and tumorigenesis.
Fig. 8: Schematic model for the mechanism by which JMJD2D activates the Hedgehog signaling to promote colonic protection, regeneration, and tumorigenesis during colitis.


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We thank Shiwen Luo (Nanchang University) for providing Gli2 expression plasmid and Hedgehog signaling reporter 8 × GBS, Chenglin Bian for TCGA data analysis, and Lei Huang for technical support. This study was supported by grants from the National Natural Science Foundation of China (no. 81970485 to CY), the National Natural Science Foundation of China (no. 81772942 to CY), the National Basic Research Program of China (973 Program, no. 2015CB553800 to CY), the National Natural Science Foundation of China (no. 81901597 to WC), the National Science and Technology Major Project of China (2017ZX10203206 to WL), the Scientific Research Foundation for Advanced Talents, Xiang’an Hospital of Xiamen University (no. PM20180917008 to WL), the Natural Science Foundation of Fujian Province (2017J01268 to XQ), and the National Health and Family Planning Commission’s Scientific Research Foundation-Health and Education cooperation foundation (WKJ2016-2-17 to XQ).

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Correspondence to Xingfeng Qiu or Wengang Li or Chundong Yu.

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All Animal experiments were conducted under protocols approved by the Laboratory Animal Center of Xiamen University. For experiments using human specimens, all specimens were anonymously coded in accordance with the Declaration of Helsinki. The study protocol that conformed to the ethical guidelines was approved by the Institute Research Ethics Committee at Xiamen University.

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Zhuo, M., Chen, W., Shang, S. et al. Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling. Oncogene 39, 3336–3353 (2020).

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