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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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https://doi.org/10.1038/s41388-021-01678-9 _ REFERENCES * Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer.

2011;11:325–37. Article  CAS  PubMed  Google Scholar  * Harris AL. Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47. Article  CAS  PubMed  Google Scholar  *

Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32. Article  CAS  PubMed  Google Scholar  * Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat

Rev Cancer. 2008;8:705–13. Article  CAS  PubMed  Google Scholar  * Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev

Cancer. 2011;12:9–22. Article  PubMed  PubMed Central  Google Scholar  * Masoud GN, Li W. HIF-1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B.

2015;5:378–89. Article  PubMed  PubMed Central  Google Scholar  * Mi C, Ma J, Wang KS, Zuo HX, Wang Z, Li MY, et al. Imperatorin suppresses proliferation and angiogenesis of human colon

cancer cell by targeting HIF-1alpha via the mTOR/p70S6K/4E-BP1 and MAPK pathways. J Ethnopharmacol. 2017;203:27–38. Article  CAS  PubMed  Google Scholar  * Epstein AC, Gleadle JM, McNeill

LA, Hewitson KS, O’Rourke J, Mole DR, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43–54. Article

  CAS  PubMed  Google Scholar  * Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by

O2-regulated prolyl hydroxylation. Science. 2001;292:468–72. Article  CAS  PubMed  Google Scholar  * Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for

VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8. Article  CAS  PubMed  Google Scholar  * Zhong H, De Marzo AM, Laughner E, Lim M,

Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 1999;59:5830–5. CAS  PubMed  Google Scholar  * Talks KL,

Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, et al. The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and

tumor-associated macrophages. Am J Pathol. 2000;157:411–21. Article  CAS  PubMed  PubMed Central  Google Scholar  * Berry WL, Janknecht R. KDM4/JMJD2 histone demethylases: epigenetic

regulators in cancer cells. Cancer Res. 2013;73:2936–42. Article  CAS  PubMed  PubMed Central  Google Scholar  * Dong F, Jiang S, Li J, Wang Y, Zhu L, Huang Y, et al. The histone demethylase

KDM4D promotes hepatic fibrogenesis by modulating Toll-like receptor 4 signaling pathway. EBioMedicine. 2019;39:472–83. Article  PubMed  Google Scholar  * Peng K, Kou L, Yu L, Bai C, Li M,

Mo P, et al. Histone demethylase JMJD2D interacts with beta-catenin to induce transcription and activate colorectal cancer cell proliferation and tumor growth in mice. Gastroenterology.

2019;156:1112–26. Article  CAS  PubMed  Google Scholar  * Zhuo M, Chen W, Shang S, Guo P, Peng K, Li M, et al. Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis

by activating Hedgehog signaling. Oncogene. 2020;39:3336–53. Article  CAS  PubMed  Google Scholar  * San-Millan I, Brooks GA. Reexamining cancer metabolism: lactate production for

carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis. 2017;38:119–33. CAS  PubMed  Google Scholar  * Peng K, Kou L, Yu L, Bai C, Li M, Mo P, et al.

Histone demethylase JMJD2D interacts with β-Catenin to Induce transcription and activate colorectal cancer cell proliferation and tumor growth in mice. Gastroenterology. 2019;156:1112–26.

Article  CAS  PubMed  Google Scholar  * Yee Koh M, Spivak-Kroizman TR, Powis G. HIF-1 regulation: not so easy come, easy go. Trends Biochem Sci. 2008;33:526–34. Article  PubMed  Google

Scholar  * Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008;8:851–64. Article  CAS  PubMed  Google Scholar  * Kim

AL, Back JH, Chaudhary SC, Zhu Y, Athar M, Bickers DR. SOX9 transcriptionally regulates mTOR-induced proliferation of basal cell carcinomas. J Invest Dermatol. 2018;138:1716–25. Article  CAS

  PubMed  PubMed Central  Google Scholar  * Hu F, Li H, Liu L, Xu F, Lai S, Luo X, et al. Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1beta/VEGFA

signalling. Mol Cancer. 2018;17:107. Article  PubMed  PubMed Central  Google Scholar  * Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22. Article  CAS

  PubMed  Google Scholar  * Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol. 2010;7:209–19. Article  CAS  PubMed  Google Scholar  * Iadevaia V, Wang X, Yao Z,

Foster LJ, Proud CG. Evaluation of mTOR-regulated mRNA translation. Methods Mol Biol. 2012;821:171–85. Article  CAS  PubMed  Google Scholar  * Wan W, Peng K, Li M, Qin L, Tong Z, Yan J, et

al. Histone demethylase JMJD1A promotes urinary bladder cancer progression by enhancing glycolysis through coactivation of hypoxia inducible factor 1α. Oncogene. 2017;36:3868–77. Article 

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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