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

Area of Science:

• Epigenetics
• Molecular Biology
• Oncology

Background:

• Histone demethylase JMJD2D regulates gene expression by removing H3K9me2/3 marks.
• The function of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) is not well understood.

Purpose of the Study:

• To investigate the role of JMJD2D in dextran sulfate sodium-induced colitis and CRC progression.
• To elucidate the underlying molecular mechanisms of JMJD2D action in the colon.

Main Methods:

• Utilized JMJD2D-deficient mice and knockdown models in CRC cells.
• Analyzed gene expression, epigenetic modifications (H3K9me3), and signaling pathways (Hedgehog).
• Examined human inflammatory bowel disease and CRC specimens for JMJD2D and Gli2 expression.

Main Results:

• Colonic JMJD2D is induced by TNFα during colitis and its deficiency exacerbates colon damage and impairs regeneration via defective Hedgehog signaling.
• JMJD2D knockdown in CRC cells inhibits growth and metastasis by suppressing Hedgehog signaling.
• JMJD2D interacts with Gli2 to decrease H3K9me3 at target gene promoters, enhancing Hedgehog pathway activity.
• JMJD2D and Gli2 are upregulated and positively correlated in human IBD and CRC samples.
• Combined inhibition of JMJD2D (5-c-8HQ, aspirin) and Hedgehog (vismodegib) synergistically reduces CRC cell proliferation and tumorigenesis.

Conclusions:

• JMJD2D plays a critical role in colonic protection, regeneration, and tumorigenesis.
• Targeting JMJD2D, particularly in combination with Hedgehog inhibitors, presents a potential therapeutic strategy for CRC.