Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer.

Autor: Venkata PP; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA., Jayamohan S; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA., He Y; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China., Alejo S; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA., Johnson JD; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA., Palacios BE; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA., Pratap UP; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA., Chen Y; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China., Liu Z; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China., Zou Y; Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, 78229, USA; Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, 78229, USA., Lai Z; Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, 78229, USA; Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, 78229, USA., Suzuki T; The Institute of Scientific and Industrial Research, Osaka University, Japan., Viswanadhapalli S; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Mays Cancer Center, UT Health San Antonio, San Antonio, TX, 78229, USA., Weintraub ST; Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, TX, 78229, USA., Palakurthi S; Department of Pharmaceutical Sciences, Texas A&M University, Kingsville, TX 78363, USA., Valente PT; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Mays Cancer Center, UT Health San Antonio, San Antonio, TX, 78229, USA., Tekmal RR; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Mays Cancer Center, UT Health San Antonio, San Antonio, TX, 78229, USA., Kost ER; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA., Vadlamudi RK; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Audie L. Murphy South Texas Veterans Health Care System, San Antonio, TX, 78229, USA; Mays Cancer Center, UT Health San Antonio, San Antonio, TX, 78229, USA., Sareddy GR; Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 78229, USA; Mays Cancer Center, UT Health San Antonio, San Antonio, TX, 78229, USA. Electronic address: sareddy@uthscsa.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2023 Oct 28; Vol. 575, pp. 216383. Date of Electronic Publication: 2023 Sep 14.
DOI: 10.1016/j.canlet.2023.216383
Abstrakt: Ovarian cancer (OCa) is the most lethal gynecologic cancer. Emerging data indicates that estrogen receptor beta (ERβ) functions as a tumor suppressor in OCa. Lysine-specific histone demethylase 1A (KDM1A) is an epigenetic modifier that acts as a coregulator for steroid hormone receptors. However, it remain unknown if KDM1A interacts with ERβ and regulates its expression/functions in OCa. Analysis of TCGA data sets indicated KDM1A and ERβ expression showed an inverse relationship in OCa. Knockout (KO), knockdown (KD), or inhibition of KDM1A increased ERβ isoform 1 expression in established and patient-derived OCa cells. Further, KDM1A interacts with and functions as a corepressor of ERβ, and its inhibition enhances ERβ target gene expression via alterations of histone methylation marks at their promoters. Importantly, KDM1A-KO or -KD enhanced the efficacy of ERβ agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) NCD38 with ERβ agonist synergistically reduced the cell viability, colony formation, and invasion of OCa cells. RNA-seq and DIA mass spectrometry analyses showed that KDM1A-KO resulted in enhanced ERβ signaling and that genes altered by KDM1A-KO and ERβ agonist were related to apoptosis, cell cycle, and EMT. Moreover, combination treatment significantly reduced the tumor growth in OCa orthotopic, syngeneic, and patient-derived xenograft models and proliferation in patient-derived explant models. Our results demonstrate that KDM1A regulates ERβ expression/functions, and its inhibition improves ERβ mediated tumor suppression. Overall, our findings suggest that KDM1Ai and ERβ agonist combination therapy is a promising strategy for OCa.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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