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

Oncogene volume 39, pages 7076–7091 (2020)Cite this article

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A Correction to this article was published on 22 February 2021

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Abstract

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.

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Fig. 1: Downregulation of JMJD2D decreases CRC glycolysis and progression through suppressing HIF1 signaling pathway.
Fig. 2: Ectopic expression of HIF1α partially rescues JMJD2D-knockdown CRC cell glycolysis, proliferation, migration, invasion, xenograft growth, and lung metastasis.
Fig. 3: JMJD2D promotes HIF1α translation through activating mTOR signaling pathway.
Fig. 4: JMJD2D cooperates with SOX9 to enhance mTOR expression.
Fig. 5: JMJD2D cooperates with c-Fos to enhance HIF1β expression.
Fig. 6: JMJD2D cooperates with HIF1α to enhance PGK1 expression.
Fig. 7: The demethylase activity of JMJD2D is required for the upregulation of mTOR, HIF1β, PGK1, LDHA, and HIF1α.
Fig. 8: The mRNA levels of JMJD2D is positively correlated with mTOR, HIF1β, and glycolytic genes in human CRC specimens.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81970485 and No. 81772942 to CY). We thank Dr Mingxia Zhu and Shuhai Lin (Xiamen University) for the technical support and reagents.

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  1. These authors contributed equally: Kesong Peng, Minghui Zhuo, Ming Li

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China

    Kesong Peng, Minghui Zhuo, Qiang Chen, Pingli Mo & Chundong Yu

  2. Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Kesong Peng

  3. Department of Hepatobiliary Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Ming Li

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Correspondence to Pingli Mo 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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Peng, K., Zhuo, M., Li, M. et al. Histone demethylase JMJD2D activates HIF1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression. Oncogene 39, 7076–7091 (2020). https://doi.org/10.1038/s41388-020-01483-w

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