Histone demethylase jmjd2d activates hif1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression

Histone demethylase jmjd2d activates hif1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression


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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. Access through your


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CAS  PubMed  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * These authors contributed equally: Kesong Peng,


Minghui Zhuo, Ming Li AUTHORS AND AFFILIATIONS * 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 * Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China


Kesong Peng * Department of Hepatobiliary Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China Ming Li Authors * Kesong Peng View author


publications You can also search for this author inPubMed Google Scholar * Minghui Zhuo View author publications You can also search for this author inPubMed Google Scholar * Ming Li View


author publications You can also search for this author inPubMed Google Scholar * Qiang Chen View author publications You can also search for this author inPubMed Google Scholar * Pingli Mo


View author publications You can also search for this author inPubMed Google Scholar * Chundong Yu View author publications You can also search for this author inPubMed Google Scholar


CORRESPONDING AUTHORS Correspondence to Pingli Mo or Chundong Yu. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ETHICAL APPROVAL 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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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 25 May 2020 * Revised: 10 September


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