Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51

Lei Tao, Yue Zhou, Xiangyu Pan, Yuan Luo, Jiahao Qiu, Xia Zhou, Zhiqian Chen, Yan Li, Lian Xu, Yang Zhou, Zeping Zuo, Chunqi Liu, Liang Wang, Xiaocong Liu, Xinyu Tian, Na Su, Zhengnan Yang, Yu Zhang, Kun Gou, Na Sang, Huan Liu, Jiao Zou, Yuzhou Xiao, Xi Zhong, Jing Xu, Xinyu Yang, Kai Xiao, Yanyang Liu, Shengyong Yang, Yong Peng, Junhong Han, Xiaobo Cen and Yinglan Zhao ()
Additional contact information
Lei Tao: West China Hospital, Sichuan University
Yue Zhou: West China Hospital, Sichuan University
Xiangyu Pan: West China Hospital, Sichuan University
Yuan Luo: West China Hospital, Sichuan University
Jiahao Qiu: West China Hospital, Sichuan University
Xia Zhou: West China Hospital, Sichuan University
Zhiqian Chen: Peking University
Yan Li: Shanxi Medical University
Lian Xu: West China Second University Hospital, Sichuan University
Yang Zhou: West China Hospital, Sichuan University
Zeping Zuo: West China Hospital, Sichuan University
Chunqi Liu: West China Hospital, Sichuan University
Liang Wang: West China Hospital, Sichuan University
Xiaocong Liu: West China Hospital, Sichuan University
Xinyu Tian: West China Hospital, Sichuan University
Na Su: Sichuan University
Zhengnan Yang: West China Hospital, Sichuan University
Yu Zhang: Tibet University
Kun Gou: West China Hospital, Sichuan University
Na Sang: West China Hospital, Sichuan University
Huan Liu: West China Hospital, Sichuan University
Jiao Zou: West China Hospital, Sichuan University
Yuzhou Xiao: West China Hospital, Sichuan University
Xi Zhong: Sichuan University
Jing Xu: West China Hospital, Sichuan University
Xinyu Yang: Sichuan University
Kai Xiao: West China Hospital, Sichuan University
Yanyang Liu: West China Hospital, Sichuan University
Shengyong Yang: West China Hospital, Sichuan University
Yong Peng: West China Hospital, Sichuan University
Junhong Han: West China Hospital, Sichuan University
Xiaobo Cen: West China Hospital, Sichuan University
Yinglan Zhao: West China Hospital, Sichuan University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42850-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42850-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42850-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().