A Specific JMJD6 Inhibitor Potently Suppresses Multiple Types of Cancers Both in Vitro and in Vivo

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Aug 15

PMID 35969736

Authors

Rong-Quan Xiao

Ting Ran

Qi-Xuan Huang

Guo-Sheng Hu

Da-Meng Fan

Jia Yi

Wen Liu

Affiliations

Soon will be listed here.

Abstract

Jumonji C-domain-containing protein 6 (JMJD6), an iron (Fe) and α-ketoglutarate (α-KG)-dependent oxygenase, is expressed at high levels, correlated with poor prognosis, and considered as a therapeutic target in multiple cancer types. However, specific JMJD6 inhibitors that are potent in suppressing tumorigenesis have not been reported so far. We herein report that iJMJD6, a specific small-molecule inhibitor of JMJD6 with favorable physiochemical properties, inhibits the enzymatic activity of JMJD6 protein both in vitro and in cultured cells. iJMJD6 is effective in suppressing cell proliferation, migration, and invasion in multiple types of cancer cells in a JMJD6-dependent manner, while it exhibits minimal toxicity in normal cells. Mechanistically, iJMJD6 represses the expression of oncogenes, including Myc and CCND1, in accordance with JMJD6 function in promoting the transcription of these genes. iJMJD6 exhibits suitable pharmacokinetic properties and suppresses tumor growth in multiple cancer cell line- and patient-derived xenograft models safely. Furthermore, combination therapy with iJMJD6 and BET protein inhibitor (BETi) JQ1 or estrogen receptor antagonist fulvestrant exhibits synergistic effects in suppressing tumor growth. Taken together, we demonstrate that inhibition of JMJD6 enzymatic activity by using iJMJD6 is effective in suppressing oncogene expression and cancer development, providing a therapeutic avenue for treating cancers that are dependent on JMJD6 in the clinic.

Citing Articles

JMJD6 K375 acetylation restrains lung cancer progression by enhancing METTL14/m6A/SLC3A2 axis mediated cell ferroptosis.

Chen H, Xiao N, Zhang C, Li Y, Zhao X, Zhang R J Transl Med. 2025; 23(1):233.

PMID: 40011892 PMC: 11863413. DOI: 10.1186/s12967-025-06241-8.

Targeting protein synthesis pathways in MYC-amplified medulloblastoma.

Kumar D, Kanchan R, Chaturvedi N Discov Oncol. 2025; 16(1):23.

PMID: 39779613 PMC: 11711608. DOI: 10.1007/s12672-025-01761-7.

Regulatory mechanisms of steroid hormone receptors on gene transcription through chromatin interaction and enhancer reprogramming.

Sun G, Zhao C, Han J, Wu S, Chen Y, Yao J Cell Oncol (Dordr). 2024; 47(6):2073-2090.

PMID: 39543064 DOI: 10.1007/s13402-024-01011-y.

Editorial: Resistance to endocrine therapies in cancer, volume II.

Chakrabarty A, Hiscox S, Ranganathan P Front Endocrinol (Lausanne). 2024; 15:1414392.

PMID: 38715800 PMC: 11074357. DOI: 10.3389/fendo.2024.1414392.

Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both and .

Huang Q, Fan D, Zheng Z, Ran T, Bai A, Xiao R J Med Chem. 2024; 67(8):6658-6672.

PMID: 38569135 PMC: 11056977. DOI: 10.1021/acs.jmedchem.4c00141.

References

Fadok V, Bratton D, Rose D, Pearson A, Ezekewitz R, Henson P . A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature. 2000; 405(6782):85-90. DOI: 10.1038/35011084. View

Yang J, Chen S, Yang Y, Ma X, Shao B, Yang S . Jumonji domain-containing protein 6 protein and its role in cancer. Cell Prolif. 2020; 53(2):e12747. PMC: 7046477. DOI: 10.1111/cpr.12747. View

Ganesan M, Tikhanovich I, Vangimalla S, Dagur R, Wang W, Poluektova L . Demethylase JMJD6 as a New Regulator of Interferon Signaling: Effects of HCV and Ethanol Metabolism. Cell Mol Gastroenterol Hepatol. 2018; 5(2):101-112. PMC: 5904050. DOI: 10.1016/j.jcmgh.2017.10.004. View

Biswas A, Mukherjee G, Kondaiah P, Desai K . Both EZH2 and JMJD6 regulate cell cycle genes in breast cancer. BMC Cancer. 2020; 20(1):1159. PMC: 7694428. DOI: 10.1186/s12885-020-07531-8. View

Wong M, Sun Y, Xi Z, Milazzo G, Poulos R, Bartenhagen C . JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nat Commun. 2019; 10(1):3319. PMC: 6658504. DOI: 10.1038/s41467-019-11132-w. View

Yi J, Shen H, Qiu J, Huang M, Zhang W, Ding J . JMJD6 and U2AF65 co-regulate alternative splicing in both JMJD6 enzymatic activity dependent and independent manner. Nucleic Acids Res. 2016; 45(6):3503-3518. PMC: 5389685. DOI: 10.1093/nar/gkw1144. View

Liu Y, Long Y, Wang S, Zhang Y, Li Y, Mi J . JMJD6 regulates histone H2A.X phosphorylation and promotes autophagy in triple-negative breast cancer cells via a novel tyrosine kinase activity. Oncogene. 2018; 38(7):980-997. DOI: 10.1038/s41388-018-0466-y. View

Zhang C, Lu X, Huang J, He H, Chen L, Liu Y . Epigenome screening highlights that JMJD6 confers an epigenetic vulnerability and mediates sunitinib sensitivity in renal cell carcinoma. Clin Transl Med. 2021; 11(2):e328. PMC: 7882098. DOI: 10.1002/ctm2.328. View

Tikhanovich I, Kuravi S, Artigues A, Villar M, Dorko K, Nawabi A . Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling. J Biol Chem. 2015; 290(36):22236-49. PMC: 4571974. DOI: 10.1074/jbc.M115.653543. View

10.

Delmore J, Issa G, Lemieux M, Rahl P, Shi J, Jacobs H . BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146(6):904-17. PMC: 3187920. DOI: 10.1016/j.cell.2011.08.017. View

11.

Webby C, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B . Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science. 2009; 325(5936):90-3. DOI: 10.1126/science.1175865. View

12.

Ran T, Xiao R, Huang Q, Yuan H, Lu T, Liu W . In Silico Discovery of JMJD6 Inhibitors for Cancer Treatment. ACS Med Chem Lett. 2019; 10(12):1609-1613. PMC: 6912872. DOI: 10.1021/acsmedchemlett.9b00264. View

13.

Chang B, Chen Y, Zhao Y, Bruick R . JMJD6 is a histone arginine demethylase. Science. 2007; 318(5849):444-7. DOI: 10.1126/science.1145801. View

14.

Pedersen M, Helin K . Histone demethylases in development and disease. Trends Cell Biol. 2010; 20(11):662-71. DOI: 10.1016/j.tcb.2010.08.011. View

15.

Hong X, Zang J, White J, Wang C, Pan C, Zhao R . Interaction of JMJD6 with single-stranded RNA. Proc Natl Acad Sci U S A. 2010; 107(33):14568-72. PMC: 2930430. DOI: 10.1073/pnas.1008832107. View

16.

Murn J, Shi Y . The winding path of protein methylation research: milestones and new frontiers. Nat Rev Mol Cell Biol. 2017; 18(8):517-527. DOI: 10.1038/nrm.2017.35. View

17.

Xiao R, Ran T, Huang Q, Hu G, Fan D, Yi J . A specific JMJD6 inhibitor potently suppresses multiple types of cancers both in vitro and in vivo. Proc Natl Acad Sci U S A. 2022; 119(34):e2200753119. PMC: 9407455. DOI: 10.1073/pnas.2200753119. View

18.

Wang F, He L, Huangyang P, Liang J, Si W, Yan R . JMJD6 promotes colon carcinogenesis through negative regulation of p53 by hydroxylation. PLoS Biol. 2014; 12(3):e1001819. PMC: 3965384. DOI: 10.1371/journal.pbio.1001819. View

19.

Miller T, Liau B, Wallace L, Morton A, Xie Q, Dixit D . Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature. 2017; 547(7663):355-359. PMC: 5896562. DOI: 10.1038/nature23000. View

20.

Kruidenier L, Chung C, Cheng Z, Liddle J, Che K, Joberty G . A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012; 488(7411):404-8. PMC: 4691848. DOI: 10.1038/nature11262. View