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Molecular carcinogenesis
Oct, 2024;63 (10): 2026-2039.

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer.

Yihong Chen, Jessica D Johnson, Sridharan Jayamohan, Yi He, Prabhakar P Venkata, Diksha Jamwal, Salvador Alejo, Yi Zou, Zhao Lai, Suryavathi Viswanadhapalli, Ratna K Vadlamudi, Edward Kost, Gangadhara R Sareddy
Author Information
  1. Yihong Chen: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  2. Jessica D Johnson: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  3. Sridharan Jayamohan: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  4. Yi He: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  5. Prabhakar P Venkata: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  6. Diksha Jamwal: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  7. Salvador Alejo: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA. ORCID
  8. Yi Zou: Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, Texas, USA.
  9. Zhao Lai: Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, Texas, USA.
  10. Suryavathi Viswanadhapalli: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  11. Ratna K Vadlamudi: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA. ORCID
  12. Edward Kost: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
  13. Gangadhara R Sareddy: Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas, USA.
PMID: 38990091 DOI: 10.1002/mc.23792

Abstract

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

Keywords

KDM1A LSD1 chemotherapy ovarian cancer

References

Int J Biochem Cell Biol. 2018 Jun;99:1-9 [PMID: 29567488]
Oncol Rep. 2022 Apr;47(4): [PMID: 35211759]
Nat Cancer. 2023 Sep;4(9):1239-1257 [PMID: 37653142]
Cancer Lett. 2023 Oct 28;575:216383 [PMID: 37714256]
Future Oncol. 2020 Mar;16(7):225-246 [PMID: 31746224]
J Hematol Oncol. 2019 Dec 4;12(1):129 [PMID: 31801559]
Cancers (Basel). 2019 Aug 15;11(8): [PMID: 31443240]
Cancer Res. 2010 May 15;70(10):4005-14 [PMID: 20424119]
Nat Rev Immunol. 2018 May;18(5):309-324 [PMID: 29379212]
Cancers (Basel). 2019 Mar 07;11(3): [PMID: 30866496]
Leukemia. 2017 Nov;31(11):2303-2314 [PMID: 28210006]
Mol Cancer Res. 2018 Oct;16(10):1458-1469 [PMID: 29934325]
Mol Cancer Res. 2019 Sep;17(9):1910-1919 [PMID: 31189689]
Neuro Oncol. 2023 Jul 6;25(7):1249-1261 [PMID: 36652263]
J Clin Oncol. 2019 Sep 20;37(27):2437-2448 [PMID: 31403868]
Cancer Lett. 2022 Jan 1;524:219-231 [PMID: 34673129]
Gynecol Oncol. 2020 Mar;156(3):654-661 [PMID: 31973910]
Exp Mol Med. 2020 Dec;52(12):1936-1947 [PMID: 33318631]
Oncol Rep. 2016 Jun;35(6):3586-92 [PMID: 27109588]
Int J Biochem Cell Biol. 2015 Apr;61:90-102 [PMID: 25681684]
Cell. 2004 Dec 29;119(7):941-53 [PMID: 15620353]
J Ovarian Res. 2015 May 09;8:28 [PMID: 25956476]
Clin Cancer Res. 2011 Apr 15;17(8):2181-94 [PMID: 21339307]
Geroscience. 2023 Jun;45(3):1889-1898 [PMID: 36856946]
Nat Rev Dis Primers. 2016 Aug 25;2:16061 [PMID: 27558151]
Breast Cancer Res Treat. 2021 Jan;185(2):343-357 [PMID: 33057995]
Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188 [PMID: 29581250]
Mol Oncol. 2023 Dec;17(12):2709-2727 [PMID: 37533407]
Cancers (Basel). 2019 Oct 17;11(10): [PMID: 31627418]
Curr Opin Cell Biol. 2008 Jun;20(3):316-25 [PMID: 18440794]
Nature. 2005 Sep 15;437(7057):436-9 [PMID: 16079795]
Biomed Res Int. 2014;2014:178410 [PMID: 24963474]
Cancer Cell. 2018 Mar 12;33(3):495-511.e12 [PMID: 29502954]
Nat Rev Clin Oncol. 2023 Dec;20(12):820-842 [PMID: 37783747]
Cancer Cell. 2015 Jul 13;28(1):57-69 [PMID: 26175415]
Epigenomics. 2017 Aug;9(8):1123-1142 [PMID: 28699367]
Oncotarget. 2013 Jan;4(1):18-28 [PMID: 23248157]
J Natl Cancer Inst. 2019 Jan 1;111(1):60-68 [PMID: 29718305]
JAMA Oncol. 2023 Jun 1;9(6):851-859 [PMID: 37079311]
CA Cancer J Clin. 2023 Jan;73(1):17-48 [PMID: 36633525]
Front Oncol. 2013 May 16;3:120 [PMID: 23720710]
Angew Chem Int Ed Engl. 2013 Aug 12;52(33):8620-4 [PMID: 23824985]
Gynecol Oncol. 2021 Oct;163(1):50-56 [PMID: 34301411]
Obstet Gynecol. 2017 Mar;129(3):439-447 [PMID: 28178043]
Endocr Relat Cancer. 2018 May;25(5):R303-R318 [PMID: 29487129]
Exp Mol Pathol. 2016 Feb;100(1):139-44 [PMID: 26683819]
Oncol Rep. 2018 Jul;40(1):425-433 [PMID: 29749504]
Sci Rep. 2015 Oct 22;5:15344 [PMID: 26489763]
Oncotarget. 2017 Jul 25;8(30):50002-50014 [PMID: 28654894]
Prostate Cancer Prostatic Dis. 2016 Dec;19(4):349-357 [PMID: 27349498]
Cancer. 2010 Jul 1;116(13):3276-84 [PMID: 20564628]

Grants

  1. NIH-1R01NS106173-01A1/National Institutes of Health:
  2. S10 OD030311/NIH HHS
  3. R50 CA265339/NCI NIH HHS
  4. T32 GM145432/NIGMS NIH HHS
  5. /Elsa U. Pardee Foundation Grant
  6. NIH-R01CA262757/National Institutes of Health:
  7. 132931-RSG-18-187-01-TBG/American Cancer Society Research Scholar Grant
  8. R01 CA266970/NCI NIH HHS
  9. R01 NS106173/NINDS NIH HHS
  10. R50-CA26533/National Institutes of Health:
  11. R01 CA262757/NCI NIH HHS
  12. NIH-R01CA266970-01A1/National Institutes of Health:
  13. NIH-T32CA148724/National Institutes of Health:
  14. T32 CA148724/NCI NIH HHS

MeSH Term

Humans
Female
Histone Demethylases
Ovarian Neoplasms
Animals
Mice
Drug Resistance, Neoplasm
Cell Line, Tumor
Paclitaxel
Cisplatin
Xenograft Model Antitumor Assays
Carboplatin
Gene Expression Regulation, Neoplastic
Apoptosis
Antineoplastic Agents
Cell Proliferation
Mice, Nude
Antineoplastic Combined Chemotherapy Protocols
Hydrazines
Sulfonamides

Chemicals

Histone Demethylases
KDM1A protein, human
Paclitaxel
Cisplatin
Carboplatin
SP2509
Antineoplastic Agents
Hydrazines
Sulfonamides
Journal Article

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