Lysine demethylase KDM3A regulates breast cancer cell invasion and apoptosis by targeting histone and the non-histone protein p53.
Invasive growth and apoptosis resistance of breast cancer cells are associated with metastasis and disease relapse. Here we identified that the lysine-specific demethylase KDM3A played a dual role in breast cancer cell invasion and apoptosis by demethylating histone and the non-histone protein p53, respectively. While inducing pro-invasive genes by erasing repressive histone H3 lysine 9 methylation, KDM3A promotes chemoresistance by demethylating p53. KDM3A suppressed pro-apoptotic functions of p53 by erasing p53-K372me1, as this methylation is crucial for the stability of chromatin-bound p53. Unexpectedly, depletion of KDM3A was capable of reactivating mutated p53 to induce the expression of pro-apoptotic genes in breast cancer with mutant p53. Moreover, KDM3A knockdown also potently inhibited tumorigenic potentials of breast cancer stem-like cells and rendered them sensitive to apoptosis induced by chemotherapeutic drugs. Taken together, our results suggest that KDM3A might be a potential therapeutic target for human breast cancer treatment and prevention.
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
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Ramadoss
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
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Guo
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.|Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA, USA.
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Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D006657:Histones; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; D008239:Lysine