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.

组蛋白去甲基化酶 JMJD2D 可以通过特异性去甲基化 H3K9me2/3 来促进基因表达。JMJD2D 在结肠炎和结肠炎相关结直肠癌 (CRC) 进展中的作用仍不清楚。在这里，我们显示结肠 JMJD2D 在硫酸葡聚糖钠诱导的结肠炎期间由 TNFα 诱导。由于结肠炎后刺猬信号激活受损，JMJD2D 缺陷小鼠表现出更严重的结肠损伤和结肠再生缺陷。CRC 细胞中的 JMJD2D 敲低抑制 Hedgehog 信号传导，导致 CRC 生长和转移减少。从机制上讲，JMJD2D 通过与 Gli2 相互作用来促进 Hedgehog 靶基因的表达，从而降低启动子的 H3K9me3 水平。临床上，人炎症性肠病标本和结直肠癌标本中 JMJD2D 表达上调并与 Gli2 表达呈正相关。JMJD2D 抑制剂 5-c-8HQ 或阿司匹林与 Hedgehog 抑制剂 vismodegib 协同抑制 CRC 细胞增殖和肿瘤发生。总的来说，我们的研究结果揭示了 JMJD2D 在激活结肠保护、再生和肿瘤发生过程中的重要作用。