Histone demethylase JMJD2D activates HIF1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression.

Hypoxia-inducible factor 1 (HIF1) signaling pathway plays a key role in cancer progression by enhancing glycolysis through activating the transcription of glycolytic genes. JMJD2D, a histone demethylase that specifically demethylates H3K9me2/3, can promote colorectal cancer (CRC) progression. However, it is unknown whether JMJD2D could promote CRC progression by enhancing glycolysis through activating HIF1 signaling pathway. In this study, we found that downregulation of JMJD2D inhibited the glycolysis in CRC cells through suppressing HIF1 signaling pathway to downregulate glycolytic gene expression. Restoring HIF1 signaling by enforced expression of HIF1α in JMJD2D-knockdown CRC cells partially recovered CRC cell glycolysis, proliferation, migration, invasion, xenograft growth, and metastasis, suggesting that JMJD2D promotes CRC progression by enhancing glycolysis through activating HIF1 signaling pathway. JMJD2D activated HIF1 signaling pathway through three different mechanisms: JMJD2D cooperated with the transcription factor SOX9 to enhance mTOR expression and then to promote HIF1α translation; JMJD2D cooperated with the transcription factor c-Fos to enhance HIF1β transcription; JMJD2D interacted and cooperated with HIF1α to enhance the expression of glycolytic gene. The demethylase-defective mutant of JMJD2D could not induce the expression of mTOR, HIF1α, HIF1β, and glycolytic genes, suggesting that the demethylase activity of JMJD2D is important for glycolysis through activating HIF1 signaling. Clinically, a highly positive correlation between the expression of JMJD2D and mTOR, HIF1β, and several glycolytic genes in human CRC specimens was identified. Collectively, our study reveals an important role of JMJD2D in CRC progression by enhancing glycolysis through activating HIF1 signaling pathway.