Histone demethylase KDM2A: Biological functions and clinical values (Review)
- Authors:
- Lisheng Liu
- Jiangnan Liu
- Qinghai Lin
-
Affiliations: Key Laboratory of Animal Resistance Research, College of Life Science, Shandong Normal University, Jinan, Shandong 250014, P.R. China, Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, SE-171 77, Sweden, Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China - Published online on: May 4, 2021 https://doi.org/10.3892/etm.2021.10155
- Article Number: 723
This article is mentioned in:
Abstract
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Luger K, Mader AW, Richmond RK, Sargent DF and Richmond TJ: Crystal structure of the nucleosome core particle at 2.8 a resolution. Nature. 389:251–260. 1997.PubMed/NCBI View Article : Google Scholar | |
Richmond TJ, Finch JT, Rushton B, Rhodes D and Klug A: Structure of the nucleosome core particle at 7 a resolution. Nature. 311:532–537. 1984.PubMed/NCBI View Article : Google Scholar | |
Hyun K, Jeon J, Park K and Kim J: Writing, erasing and reading histone lysine methylations. Exp Mol Med. 49(e324)2017.PubMed/NCBI View Article : Google Scholar | |
Black JC, Van Rechem C and Whetstine JR: Histone lysine methylation dynamics: Establishment, regulation, and biological impact. Mol Cell. 48:491–507. 2012.PubMed/NCBI View Article : Google Scholar | |
Hojfeldt JW, Agger K and Helin K: Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 12:917–930. 2013.PubMed/NCBI View Article : Google Scholar | |
Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA and Shi Y: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 119:941–953. 2004.PubMed/NCBI View Article : Google Scholar | |
Fang Y, Liao G and Yu B: Targeting histone lysine demethylase LSD1/KDM1A as a new avenue for cancer therapy. Curr Top Med Chem. 19:889–891. 2019.PubMed/NCBI View Article : Google Scholar | |
Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P and Zhang Y: Histone demethylation by a family of JmjC domain-containing proteins. Nature. 439:811–816. 2006.PubMed/NCBI View Article : Google Scholar | |
Xiang Y, Zhu Z, Han G, Ye X, Xu B, Peng Z, Ma Y, Yu Y, Lin H, Chen AP and Chen CD: JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc Natl Acad Sci USA. 104:19226–19231. 2007.PubMed/NCBI View Article : Google Scholar | |
Klose RJ, Kallin EM and Zhang Y: JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 7:715–727. 2006.PubMed/NCBI View Article : Google Scholar | |
Cloos PA, Christensen J, Agger K and Helin K: Erasing the methyl mark: Histone demethylases at the center of cellular differentiation and disease. Genes Dev. 22:1115–1140. 2008.PubMed/NCBI View Article : Google Scholar | |
Vacik T, Ladinovic D and Raska I: KDM2A/B lysine demethylases and their alternative isoforms in development and disease. Nucleus. 9:431–441. 2018.PubMed/NCBI View Article : Google Scholar | |
Zlotorynski E: Protein folding: Structure-function analysis of KDM2A. Nat Rev Mol Cell Biol. 15(630)2014.PubMed/NCBI View Article : Google Scholar | |
Blackledge NP, Zhou JC, Tolstorukov MY, Farcas AM, Park PJ and Klose RJ: CpG islands recruit a histone H3 lysine 36 demethylase. Mol Cell. 38:179–190. 2010.PubMed/NCBI View Article : Google Scholar | |
Zhou JC, Blackledge NP, Farcas AM and Klose RJ: Recognition of CpG island chromatin by KDM2A requires direct and specific interaction with linker DNA. Mol Cell Biol. 32:479–489. 2012.PubMed/NCBI View Article : Google Scholar | |
Iuchi S and Paulo JA: Lysine-specific demethylase 2A enhances binding of various nuclear factors to CpG-rich genomic DNAs by action of its CXXC-PHD domain. Sci Rep. 9(5496)2019.PubMed/NCBI View Article : Google Scholar | |
Liu H, Liu L, Holowatyj A, Jiang Y and Yang ZQ: Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer. Mol Carcinog. 55:977–990. 2016.PubMed/NCBI View Article : Google Scholar | |
Cheng Z, Cheung P, Kuo AJ, Yukl ET, Wilmot CM, Gozani O and Patel DJ: A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36. Genes Dev. 28:1758–1771. 2014.PubMed/NCBI View Article : Google Scholar | |
Iuchi S and Green H: Lysine-specific demethylase 2A (KDM2A) normalizes human embryonic stem cell derived keratinocytes. Proc Natl Acad Sci USA. 109:9442–9447. 2012.PubMed/NCBI View Article : Google Scholar | |
Ladinovic D, Pinkas D, Šopin T, Raška O, Liška F, Raška I and Vacík T: Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling. PLoS One. 15(e236612)2020.PubMed/NCBI View Article : Google Scholar | |
Frescas D, Guardavaccaro D, Kuchay SM, Kato H, Poleshko A, Basrur V, Elenitoba-Johnson KS, Katz RA and Pagano M: KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state. Cell Cycle. 7:3539–3547. 2008.PubMed/NCBI View Article : Google Scholar | |
Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N and Ohara O: Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6:63–70. 1999.PubMed/NCBI View Article : Google Scholar | |
Chen JY, Luo CW, Lai YS, Wu CC and Hung WC: Lysine demethylase KDM2A inhibits TET2 to promote DNA methylation and silencing of tumor suppressor genes in breast cancer. Oncogenesis. 6(e369)2017.PubMed/NCBI View Article : Google Scholar | |
Kong Y, Zou S, Yang F, Xu X, Bu W, Jia J and Liu Z: RUNX3-mediated up-regulation of miR-29b suppresses the proliferation and migration of gastric cancer cells by targeting KDM2A. Cancer Lett. 381:138–148. 2016.PubMed/NCBI View Article : Google Scholar | |
Dhar SS, Alam H, Li N, Wagner KW, Chung J, Ahn YW and Lee MG: Transcriptional repression of histone deacetylase 3 by the histone demethylase KDM2A is coupled to tumorigenicity of lung cancer cells. J Biol Chem. 289:7483–7496. 2014.PubMed/NCBI View Article : Google Scholar | |
Tanaka Y, Obinata H, Konishi A, Yamagiwa N and Tsuneoka M: Production of ROS by Gallic acid activates KDM2A to reduce rRNA transcription. Cells. 9(2266)2020.PubMed/NCBI View Article : Google Scholar | |
Tanaka Y, Konishi A, Obinata H and Tsuneoka M: Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level. Sci Rep. 9(18694)2019.PubMed/NCBI View Article : Google Scholar | |
Wang F, Liang S, Liu X, Han L, Wang J and Du Q: LINC00460 modulates KDM2A to promote cell proliferation and migration by targeting miR-342-3p in gastric cancer. Onco Targets Ther. 11:6383–6394. 2018.PubMed/NCBI View Article : Google Scholar | |
Shou T, Yang H, Lv J, Liu D and Sun X: MicroRNA3666 suppresses the growth and migration of glioblastoma cells by targeting KDM2A. Mol Med Rep. 19:1049–1055. 2019.PubMed/NCBI View Article : Google Scholar | |
Li X, Wei C, Zhang Z, Jin Q and Xiao X: MiR-134-5p regulates myocardial apoptosis and angiogenesis by directly targeting KDM2A After myocardial infarction. Int Heart J. 61:815–821. 2020.PubMed/NCBI View Article : Google Scholar | |
Zhao Y, Chen X, Jiang J, Wan X, Wang Y and Xu P: Epigallocatechin gallate reverses gastric cancer by regulating the long noncoding RNA LINC00511/miR-29b/KDM2A axis. Biochim Biophys Acta Mol Basis Dis. 1866(165856)2020.PubMed/NCBI View Article : Google Scholar | |
Yang H, Li G, Han N, Zhang X, Cao Y, Cao Y and Fan Z: Secreted frizzled-related protein 2 promotes the osteo/odontogenic differentiation and paracrine potentials of stem cells from apical papilla under inflammation and hypoxia conditions. Cell Prolif. 53(e12694)2020.PubMed/NCBI View Article : Google Scholar | |
Ou R, Zhu L, Zhao L, Li W, Tao F, Lu Y, He Q, Li J, Ren Y and Xu Y: HPV16 E7-induced upregulation of KDM2A promotes cervical cancer progression by regulating miR-132-radixin pathway. J Cell Physiol. 234:2659–2671. 2019.PubMed/NCBI View Article : Google Scholar | |
Wang Y, Sun B, Zhang Q, Dong H and Zhang J: p300 Acetylates JHDM1A to inhibit osteosarcoma carcinogenesis. Artif Cells Nanomed Biotechnol. 47:2891–2899. 2019.PubMed/NCBI View Article : Google Scholar | |
Tanaka Y, Yano H, Ogasawara S, Yoshioka S, Imamura H, Okamoto K and Tsuneoka M: Mild glucose starvation induces KDM2A-mediated H3K36me2 demethylation through AMPK To reduce rRNA transcription and cell proliferation. Mol Cell Biol. 35:4170–4184. 2015.PubMed/NCBI View Article : Google Scholar | |
Lu S, Yang Y, Du Y, Cao LL, Li M, Shen C, Hou T, Zhao Y, Wang H, Deng D, et al: The transcription factor c-Fos coordinates with histone lysine-specific demethylase 2A to activate the expression of cyclooxygenase-2. Oncotarget. 6:34704–34717. 2015.PubMed/NCBI View Article : Google Scholar | |
McAllister TE, England KS, Hopkinson RJ, Brennan PE, Kawamura A and Schofield CJ: Recent progress in histone demethylase inhibitors. J Med Chem. 59:1308–1329. 2016.PubMed/NCBI View Article : Google Scholar | |
Suzuki T, Ozasa H, Itoh Y, Zhan P, Sawada H, Mino K, Walport L, Ohkubo R, Kawamura A, Yonezawa M, et al: Identification of the KDM2/7 histone lysine demethylase subfamily inhibitor and its antiproliferative activity. J Med Chem. 56:7222–7231. 2013.PubMed/NCBI View Article : Google Scholar | |
Gerken PA, Wolstenhulme JR, Tumber A, Hatch SB, Zhang Y, Müller S, Chandler SA, Mair B, Li F, Nijman SMB, et al: Discovery of a highly selective cell-active inhibitor of the histone lysine demethylases KDM2/7. Angew Chem Int Ed Engl. 56:15555–15559. 2017.PubMed/NCBI View Article : Google Scholar | |
Zhou Q, Chen L, Song Y, Ma L, Xiao P, Chen L, Zhen H, Han R, Chen X, Sun S, et al: Induction of co-inhibitory molecule CTLA-4 by human papillomavirus E7 protein through downregulation of histone methyltransferase JHDM1B expression. Virology. 538:111–118. 2019.PubMed/NCBI View Article : Google Scholar | |
Abdel-Hameed EA, Ji H and Shata MT: HIV-induced epigenetic alterations in host cells. Adv Exp Med Biol. 879:27–38. 2016.PubMed/NCBI View Article : Google Scholar | |
Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, Li Y, Chen H, Yang H, Hsu PH, et al: LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 174:549–563.e19. 2018.PubMed/NCBI View Article : Google Scholar | |
Boehm D and Ott M: Host methyltransferases and demethylases: Potential new epigenetic targets for HIV cure strategies and beyond. AIDS Res Hum Retroviruses. 33 (Suppl):S8–S22. 2017.PubMed/NCBI View Article : Google Scholar | |
Rose NR, Woon EC, Tumber A, Walport LJ, Chowdhury R, Li XS, King ON, Lejeune C, Ng SS, Krojer T, et al: Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. J Med Chem. 55:6639–6643. 2012.PubMed/NCBI View Article : Google Scholar | |
Chen JY, Li CF, Chu PY, Lai YS, Chen CH, Jiang SS, Hou MF and Hung WC: Lysine demethylase 2A promotes stemness and angiogenesis of breast cancer by upregulating Jagged1. Oncotarget. 7:27689–27710. 2016.PubMed/NCBI View Article : Google Scholar | |
Wagner KW, Alam H, Dhar SS, Giri U, Li N, Wei Y, Giri D, Cascone T, Kim JH, Ye Y, et al: KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest. 123:5231–5246. 2013.PubMed/NCBI View Article : Google Scholar | |
Huang Y, Liu Y, Yu L, Chen J, Hou J, Cui L, Ma D and Lu W: Histone demethylase KDM2A promotes tumor cell growth and migration in gastric cancer. Tumour Biol. 36:271–278. 2015.PubMed/NCBI View Article : Google Scholar | |
Lu DH, Yang J, Gao LK, Min J, Tang JM, Hu M, Li Y, Li ST, Chen J and Hong L: Lysine demethylase 2A promotes the progression of ovarian cancer by regulating the PI3K pathway and reversing epithelialmesenchymal transition. Oncol Rep. 41:917–927. 2019.PubMed/NCBI View Article : Google Scholar | |
Xi C, Ye NY and Wang YB: LncRNA LINC01278 accelerates colorectal cancer progression via miR-134-5p/KDM2A axis. Eur Rev Med Pharmacol Sci. 24:10526–10534. 2020.PubMed/NCBI View Article : Google Scholar | |
Cao LL, Du C, Liu H, Pei L, Qin L, Jia M and Wang H: Lysine-specific demethylase 2A expression is associated with cell growth and cyclin D1 expression in colorectal adenocarcinoma. Int J Biol Markers: Apr 1, 2018 (Epub ahead of print). doi: 10.1177/1724600818764069. | |
Rizwani W, Schaal C, Kunigal S, Coppola D and Chellappan S: Mammalian lysine histone demethylase KDM2A regulates E2F1-mediated gene transcription in breast cancer cells. PLoS One. 9(e100888)2014.PubMed/NCBI View Article : Google Scholar | |
Chen JY, Li CF, Lai YS and Hung WC: Lysine demethylase 2A expression in cancer-associated fibroblasts promotes breast tumour growth. Br J Cancer. 124:484–493. 2020.PubMed/NCBI View Article : Google Scholar | |
De Nicola I, Guerrieri AN, Penzo M, Ceccarelli C, De Leo A, Trerè D and Montanaro L: Combined expression levels of KDM2A and KDM2B correlate with nucleolar size and prognosis in primary breast carcinomas. Histol Histopathol. 35:1181–1187. 2020.PubMed/NCBI View Article : Google Scholar | |
Lin Q, Wu Z, Yue X, Yu X, Wang Z, Song X, Xu L, He Y, Ge Y, Tan S, et al: ZHX2 restricts hepatocellular carcinoma by suppressing stem cell-like traits through KDM2A-mediated H3K36 demethylation. Ebiomedicine. 53(102676)2020.PubMed/NCBI View Article : Google Scholar | |
Scahill CM, Digby Z, Sealy IM, Wojciechowska S, White RJ, Collins JE, Stemple DL, Bartke T, Mathers ME, Patton EE and Busch-Nentwich EM: Loss of the chromatin modifier Kdm2aa causes BrafV600E-independent spontaneous melanoma in zebrafish. PLoS Genet. 13(e1006959)2017.PubMed/NCBI View Article : Google Scholar | |
Lu T, Jackson MW, Singhi AD, Kandel ES, Yang M, Zhang Y, Gudkov AV and Stark GR: Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkappaB. Proc Natl Acad Sci USA. 106:16339–16344. 2009.PubMed/NCBI View Article : Google Scholar | |
Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, Gudkov AV and Stark GR: Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci USA. 107:46–51. 2010.PubMed/NCBI View Article : Google Scholar | |
Gao R, Dong R, Du J, Ma P, Wang S and Fan Z: Depletion of histone demethylase KDM2A inhibited cell proliferation of stem cells from apical papilla by de-repression of p15INK4B and p27Kip1. Mol Cell Biochem. 379:115–122. 2013.PubMed/NCBI View Article : Google Scholar | |
Dong R, Yao R, Du J, Wang S and Fan Z: Depletion of histone demethylase KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of stem cells from apical papilla. Exp Cell Res. 319:2874–2882. 2013.PubMed/NCBI View Article : Google Scholar | |
Yu G, Wang J, Lin X, Diao S, Cao Y, Dong R, Wang L, Wang S and Fan Z: Demethylation of SFRP2 by histone demethylase KDM2A regulated osteo-/dentinogenic differentiation of stem cells of the apical papilla. Cell Prolif. 49:330–340. 2016.PubMed/NCBI View Article : Google Scholar | |
Du J, Ma Y, Ma P, Wang S and Fan Z: Demethylation of epiregulin gene by histone demethylase FBXL11 and BCL6 corepressor inhibits osteo/dentinogenic differentiation. Stem Cells. 31:126–136. 2013.PubMed/NCBI View Article : Google Scholar | |
Wang T, Chen K, Zeng X, Yang J, Wu Y, Shi X, Qin B, Zeng L, Esteban MA, Pan G and Pei D: The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell. 9:575–587. 2011.PubMed/NCBI View Article : Google Scholar | |
Yi Q, Cao Y, Liu OS, Lu YQ, Wang JS, Wang SL, Yao R and Fan ZP: Spatial and temporal expression of histone demethylase, Kdm2a, during murine molar development. Biotech Histochem. 91:137–144. 2016.PubMed/NCBI View Article : Google Scholar | |
Kawakami E, Tokunaga A, Ozawa M, Sakamoto R and Yoshida N: The histone demethylase Fbxl11/Kdm2a plays an essential role in embryonic development by repressing cell-cycle regulators. Mech Dev. 135:31–42. 2015.PubMed/NCBI View Article : Google Scholar | |
Fu E, Shen J, Dong Z, Zhang W, Zhang Y, Chen F, Cheng Z, Zhao X, Shuai L and Lu X: Histone demethylase Kdm2a regulates germ cell genes and endogenous retroviruses in embryonic stem cells. Epigenomics. 11:751–766. 2019.PubMed/NCBI View Article : Google Scholar | |
Lu L, Gao Y, Zhang Z, Cao Q, Zhang X, Zou J and Cao Y: Kdm2a/b lysine demethylases regulate canonical Wnt signaling by modulating the stability of nuclear β-catenin. Dev Cell. 33:660–674. 2015.PubMed/NCBI View Article : Google Scholar | |
Acevedo N, Reinius LE, Vitezic M, Fortino V, Söderhäll C, Honkanen H, Veijola R, Simell O, Toppari J, Ilonen J, et al: Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes. Clin Epigenetics. 7(34)2015.PubMed/NCBI View Article : Google Scholar | |
Salminen A, Kauppinen A and Kaarniranta K: 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: Potential role in the regulation of aging process. Cell Mol Life Sci. 72:3897–3914. 2015.PubMed/NCBI View Article : Google Scholar | |
Pan D, Mao C, Zou T, Yao AY, Cooper MP, Boyartchuk V and Wang YX: The histone demethylase Jhdm1a regulates hepatic gluconeogenesis. PLoS Genet. 8(e1002761)2012.PubMed/NCBI View Article : Google Scholar | |
Tanaka Y, Okamoto K, Teye K, Umata T, Yamagiwa N, Suto Y, Zhang Y and Tsuneoka M: JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation. EMBO J. 29:1510–1522. 2010.PubMed/NCBI View Article : Google Scholar | |
Tanaka Y, Umata T, Okamoto K, Obuse C and Tsuneoka M: CxxC-ZF domain is needed for KDM2A to demethylate histone in rDNA promoter in response to starvation. Cell Struct Funct. 39:79–92. 2014.PubMed/NCBI View Article : Google Scholar | |
Tsuneoka M, Tanaka Y and Okamoto K: A CxxC domain that binds to unmethylated CpG is required for KDM2A to control rDNA transcription. Yakugaku Zasshi. 135:11–21. 2015.PubMed/NCBI View Article : Google Scholar : (In Japanese). | |
Reischl S and Kramer A: Fbxl11 is a novel negative element of the mammalian circadian clock. J Biol Rhythms. 30:291–301. 2015.PubMed/NCBI View Article : Google Scholar | |
Jin MH and Oh DY: ATM in DNA repair in cancer. Pharmacol Ther. 203(107391)2019.PubMed/NCBI View Article : Google Scholar | |
Cao LL, Wei F, Du Y, Song B, Wang D, Shen C, Lu X, Cao Z, Yang Q, Gao Y, et al: ATM-mediated KDM2A phosphorylation is required for the DNA damage repair. Oncogene. 35(402)2016.PubMed/NCBI View Article : Google Scholar | |
Bueno M, Baldascini M, Richard S and Lowndes NF: Recruitment of lysine demethylase 2A to DNA double strand breaks and its interaction with 53BP1 ensures genome stability. Oncotarget. 9:15915–15930. 2018.PubMed/NCBI View Article : Google Scholar | |
Rezazadeh S, Yang D, Biashad SA, Firsanov D, Takasugi M, Gilbert M, Tombline G, Bhanu NV, Garcia BA, Seluanov A and Gorbunova V: SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA damage sites to inhibit transcription and promote repair. Aging (Albany NY). 12:11165–11184. 2020.PubMed/NCBI View Article : Google Scholar |