PMID- 37714256
OWN - NLM
STAT- MEDLINE
DCOM- 20231011
LR  - 20231018
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 575
DP  - 2023 Oct 28
TI  - Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated 
      tumor suppression in ovarian cancer.
PG  - 216383
LID - S0304-3835(23)00334-8 [pii]
LID - 10.1016/j.canlet.2023.216383 [doi]
AB  - Ovarian cancer (OCa) is the most lethal gynecologic cancer. Emerging data 
      indicates that estrogen receptor beta (ERbeta) 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 ERbeta and regulates its expression/functions in 
      OCa. Analysis of TCGA data sets indicated KDM1A and ERbeta expression showed an 
      inverse relationship in OCa. Knockout (KO), knockdown (KD), or inhibition of 
      KDM1A increased ERbeta isoform 1 expression in established and patient-derived OCa 
      cells. Further, KDM1A interacts with and functions as a corepressor of ERbeta, and 
      its inhibition enhances ERbeta target gene expression via alterations of histone 
      methylation marks at their promoters. Importantly, KDM1A-KO or -KD enhanced the 
      efficacy of ERbeta agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) 
      NCD38 with ERbeta 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 ERbeta signaling and that genes altered by 
      KDM1A-KO and ERbeta 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 ERbeta 
      expression/functions, and its inhibition improves ERbeta mediated tumor suppression. 
      Overall, our findings suggest that KDM1Ai and ERbeta agonist combination therapy is 
      a promising strategy for OCa.
CI  - Copyright (c) 2023 Elsevier B.V. All rights reserved.
FAU - Venkata, Prabhakar Pitta
AU  - Venkata PP
AD  - Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 
      78229, USA.
FAU - Jayamohan, Sridharan
AU  - Jayamohan S
AD  - Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 
      78229, USA.
FAU - He, Yi
AU  - He Y
AD  - 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.
FAU - Alejo, Salvador
AU  - Alejo S
AD  - Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 
      78229, USA.
FAU - Johnson, Jessica D
AU  - Johnson JD
AD  - Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 
      78229, USA.
FAU - Palacios, Bridgitte E
AU  - Palacios BE
AD  - Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 
      78229, USA.
FAU - Pratap, Uday P
AU  - Pratap UP
AD  - Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 
      78229, USA.
FAU - Chen, Yihong
AU  - Chen Y
AD  - 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.
FAU - Liu, Zexuan
AU  - Liu Z
AD  - 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.
FAU - Zou, Yi
AU  - Zou Y
AD  - 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.
FAU - Lai, Zhao
AU  - Lai Z
AD  - 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.
FAU - Suzuki, Takayoshi
AU  - Suzuki T
AD  - The Institute of Scientific and Industrial Research, Osaka University, Japan.
FAU - Viswanadhapalli, Suryavathi
AU  - Viswanadhapalli S
AD  - 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.
FAU - Weintraub, Susan T
AU  - Weintraub ST
AD  - Department of Biochemistry and Structural Biology, UT Health San Antonio, San 
      Antonio, TX, 78229, USA.
FAU - Palakurthi, Srinath
AU  - Palakurthi S
AD  - Department of Pharmaceutical Sciences, Texas A&M University, Kingsville, TX 
      78363, USA.
FAU - Valente, Philip T
AU  - Valente PT
AD  - 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.
FAU - Tekmal, Rajeshwar R
AU  - Tekmal RR
AD  - 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.
FAU - Kost, Edward R
AU  - Kost ER
AD  - Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, 
      78229, USA.
FAU - Vadlamudi, Ratna K
AU  - Vadlamudi RK
AD  - 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.
FAU - Sareddy, Gangadhara R
AU  - Sareddy GR
AD  - 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.
LA  - eng
GR  - R50 CA265339/CA/NCI NIH HHS/United States
GR  - T32 CA148724/CA/NCI NIH HHS/United States
GR  - R01 CA269866/CA/NCI NIH HHS/United States
GR  - R01 NS106173/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230914
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (Estrogens)
RN  - EC 1.14.11.- (Histone Demethylases)
RN  - EC 1.5.- (KDM1A protein, human)
SB  - IM
MH  - Humans
MH  - Female
MH  - *Estrogen Receptor beta/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Genes, Tumor Suppressor
MH  - *Ovarian Neoplasms/drug therapy/genetics
MH  - Estrogens
MH  - Histone Demethylases
OTO - NOTNLM
OT  - Combination therapy
OT  - Estrogen receptor beta
OT  - KDM1A
OT  - LSD1
OT  - Ovarian cancer
COIS- 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.
EDAT- 2023/09/16 05:42
MHDA- 2023/10/11 06:45
CRDT- 2023/09/15 19:12
PHST- 2023/06/19 00:00 [received]
PHST- 2023/08/19 00:00 [revised]
PHST- 2023/09/07 00:00 [accepted]
PHST- 2023/10/11 06:45 [medline]
PHST- 2023/09/16 05:42 [pubmed]
PHST- 2023/09/15 19:12 [entrez]
AID - S0304-3835(23)00334-8 [pii]
AID - 10.1016/j.canlet.2023.216383 [doi]
PST - ppublish
SO  - Cancer Lett. 2023 Oct 28;575:216383. doi: 10.1016/j.canlet.2023.216383. Epub 2023 
      Sep 14.