Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance.
Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively. In addition, KDM3A induces ovarian cancer growth while antagonizing cellular senescence by repressing the expression of cyclin-dependent kinase inhibitor, p21Waf1/Cip1. The underlying mechanism of the noted biological processes include KDM3A-mediated stimulation of Sox2 expression, and demethylating p53 protein and consequently, modulating its target genes such as Bcl-2 and p21Waf1/Cip1expression. Consistently, KDM3A depletion inhibited the growth of subcutaneously implanted cisplatin-resistant human ovarian cancer cells in athymic nude mice. Moreover, KDM3A is abundantly expressed and positively correlated with Sox2 expression in human ovarian cancer tissues. In brief, our findings reveal a novel mechanism by which KDM3A promotes ovarian CSCs, proliferation and chemoresistance and thus, highlights the significance of KDM3A as a novel therapeutic target for resistant ovarian cancer.
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
S
S
Ramadoss
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
S
S
Sen
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, Tamil Nadu, India.
I
I
Ramachandran
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
S
S
Roy
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.|Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
G
G
Chaudhuri
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
R
R
Farias-Eisner
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019253:Proto-Oncogene Proteins c-bcl-2; D055748:SOXB1 Transcription Factors; D016159:Tumor Suppressor Protein p53; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; D008239:Lysine; D002945:Cisplatin
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