Screen-identified Selective Inhibitor of Lysine Demethylase 5A Blocks Cancer Cell Growth and Drug Resistance

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 May 26

PMID 27224921

Citations 46

Authors

Molly Gale

Joyce Sayegh

Jian Cao

Michael Norcia

Peter Gareiss

Denton Hoyer

Jane S Merkel

Qin Yan

Affiliations

Soon will be listed here.

Abstract

Lysine demethylase 5A (KDM5A/RBP2/JARID1A) is a histone lysine demethylase that is overexpressed in several human cancers including lung, gastric, breast and liver cancers. It plays key roles in important cancer processes including tumorigenesis, metastasis, and drug tolerance, making it a potential cancer therapeutic target. Chemical tools to analyze KDM5A demethylase activity are extremely limited as available inhibitors are not specific for KDM5A. Here, we characterized KDM5A using a homogeneous luminescence-based assay and conducted a screen of about 9,000 small molecules for inhibitors. From this screen, we identified several 3-thio-1,2,4-triazole compounds that inhibited KDM5A with low μM in vitro IC50 values. Importantly, these compounds showed great specificity and did not inhibit its close homologue KDM5B (PLU1/JARID1B) or the related H3K27 demethylases KDM6A (UTX) and KDM6B (JMJD3). One compound, named YUKA1, was able to increase H3K4me3 levels in human cells and selectively inhibit the proliferation of cancer cells whose growth depends on KDM5A. As KDM5A was shown to mediate drug tolerance, we investigated the ability of YUKA1 to prevent drug tolerance in EGFR-mutant lung cancer cells treated with gefitinib and HER2+ breast cancer cells treated with trastuzumab. Remarkably, this compound hindered the emergence of drug-tolerant cells, highlighting the critical role of KDM5A demethylase activity in drug resistance. The small molecules presented here are excellent tool compounds for further study of KDM5A's demethylase activity and its contributions to cancer.

Citing Articles

KDM5 family as therapeutic targets in breast cancer: Pathogenesis and therapeutic opportunities and challenges.

Li C, Wang W, Leung C, Yang G, Chen J Mol Cancer. 2024; 23(1):109.

PMID: 38769556 PMC: 11103982. DOI: 10.1186/s12943-024-02011-0.

Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth.

Chen H, Jin W Medicina (Kaunas). 2024; 60(2).

PMID: 38399515 PMC: 10890489. DOI: 10.3390/medicina60020228.

Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance.

Bhat G, Sethi I, Sadida H, Rah B, Mir R, Algehainy N Cancer Metastasis Rev. 2024; 43(1):197-228.

PMID: 38329598 PMC: 11016008. DOI: 10.1007/s10555-024-10172-z.

Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities.

De Marco K, Sanese P, Simone C, Grossi V Cancers (Basel). 2023; 15(20).

PMID: 37894343 PMC: 10605360. DOI: 10.3390/cancers15204976.

MicroRNA-495: a therapeutic and diagnostic tumor marker.

Maharati A, Tolue Ghasaban F, Akhlaghipour I, Taghehchian N, Zangouei A, Moghbeli M J Mol Histol. 2023; 54(6):559-578.

PMID: 37759132 DOI: 10.1007/s10735-023-10159-0.

References

Baell J, Holloway G . New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010; 53(7):2719-40. DOI: 10.1021/jm901137j. View

Horton J, Engstrom A, Zoeller E, Liu X, Shanks J, Zhang X . Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases. J Biol Chem. 2015; 291(6):2631-46. PMC: 4742734. DOI: 10.1074/jbc.M115.698449. View

Yamane K, Tateishi K, Klose R, Fang J, Fabrizio L, Erdjument-Bromage H . PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol Cell. 2007; 25(6):801-12. DOI: 10.1016/j.molcel.2007.03.001. View

Kawamura A, Tumber A, Rose N, King O, Daniel M, Oppermann U . Development of homogeneous luminescence assays for histone demethylase catalysis and binding. Anal Biochem. 2010; 404(1):86-93. PMC: 4673899. DOI: 10.1016/j.ab.2010.04.030. View

Zeng J, Ge Z, Wang L, Li Q, Wang N, Bjorkholm M . The histone demethylase RBP2 Is overexpressed in gastric cancer and its inhibition triggers senescence of cancer cells. Gastroenterology. 2009; 138(3):981-92. DOI: 10.1053/j.gastro.2009.10.004. View

Tsukada Y, Fang J, Erdjument-Bromage H, Warren M, Borchers C, Tempst P . Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2005; 439(7078):811-6. DOI: 10.1038/nature04433. View

Hou J, Wu J, Dombkowski A, Zhang K, Holowatyj A, Boerner J . Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer. Am J Transl Res. 2012; 4(3):247-56. PMC: 3426386. View

Teng Y, Lee C, Li Y, Chen Y, Hsiao P, Chan M . Histone demethylase RBP2 promotes lung tumorigenesis and cancer metastasis. Cancer Res. 2013; 73(15):4711-21. DOI: 10.1158/0008-5472.CAN-12-3165. View

Banelli B, Carra E, Barbieri F, Wurth R, Parodi F, Pattarozzi A . The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma. Cell Cycle. 2015; 14(21):3418-29. PMC: 4825557. DOI: 10.1080/15384101.2015.1090063. View

10.

Rasmussen P, Staller P . The KDM5 family of histone demethylases as targets in oncology drug discovery. Epigenomics. 2014; 6(3):277-86. DOI: 10.2217/epi.14.14. View

11.

Sakurai M, Rose N, Schultz L, Quinn A, Jadhav A, Ng S . A miniaturized screen for inhibitors of Jumonji histone demethylases. Mol Biosyst. 2010; 6(2):357-64. PMC: 3401096. DOI: 10.1039/b912993f. View

12.

Suzuki T, Miyata N . Lysine demethylases inhibitors. J Med Chem. 2011; 54(24):8236-50. DOI: 10.1021/jm201048w. View

13.

Gale M, Yan Q . High-throughput screening to identify inhibitors of lysine demethylases. Epigenomics. 2015; 7(1):57-65. PMC: 4356004. DOI: 10.2217/epi.14.63. View

14.

Wang S, Wang Y, Wu H, Hu L . RBP2 induces epithelial-mesenchymal transition in non-small cell lung cancer. PLoS One. 2013; 8(12):e84735. PMC: 3869927. DOI: 10.1371/journal.pone.0084735. View

15.

Bavetsias V, Lanigan R, Ruda G, Atrash B, McLaughlin M, Tumber A . 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. J Med Chem. 2016; 59(4):1388-409. PMC: 4770324. DOI: 10.1021/acs.jmedchem.5b01635. View

16.

Cao J, Liu Z, Cheung W, Zhao M, Chen S, Chan S . Histone demethylase RBP2 is critical for breast cancer progression and metastasis. Cell Rep. 2014; 6(5):868-77. PMC: 4014129. DOI: 10.1016/j.celrep.2014.02.004. View

17.

Sayegh J, Cao J, Zou M, Morales A, Blair L, Norcia M . Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J Biol Chem. 2013; 288(13):9408-17. PMC: 3611010. DOI: 10.1074/jbc.M112.419861. View

18.

van Oevelen C, Wang J, Asp P, Yan Q, Kaelin Jr W, Kluger Y . A role for mammalian Sin3 in permanent gene silencing. Mol Cell. 2008; 32(3):359-70. PMC: 3100182. DOI: 10.1016/j.molcel.2008.10.015. View

19.

Lin W, Cao J, Liu J, Beshiri M, Fujiwara Y, Francis J . Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci U S A. 2011; 108(33):13379-86. PMC: 3158206. DOI: 10.1073/pnas.1110104108. View

20.

Itoh Y, Sawada H, Suzuki M, Tojo T, Sasaki R, Hasegawa M . Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells. ACS Med Chem Lett. 2015; 6(6):665-70. PMC: 4468397. DOI: 10.1021/acsmedchemlett.5b00083. View