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C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer

PARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transc...

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Autores principales: Tan, Jiahong, Zheng, Xu, Li, Mengchen, Ye, Fei, Song, Chunyan, Xu, Cheng, Zhang, Xiaoxue, Li, Wenqian, Wang, Ya, Zeng, Shaoqing, Li, Huayi, Chen, Gang, Huang, Xiaoyuan, Ma, Ding, Liu, Dan, Gao, Qinglei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175237/
https://www.ncbi.nlm.nih.gov/pubmed/33966038
http://dx.doi.org/10.1038/s41388-021-01788-4
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author Tan, Jiahong
Zheng, Xu
Li, Mengchen
Ye, Fei
Song, Chunyan
Xu, Cheng
Zhang, Xiaoxue
Li, Wenqian
Wang, Ya
Zeng, Shaoqing
Li, Huayi
Chen, Gang
Huang, Xiaoyuan
Ma, Ding
Liu, Dan
Gao, Qinglei
author_facet Tan, Jiahong
Zheng, Xu
Li, Mengchen
Ye, Fei
Song, Chunyan
Xu, Cheng
Zhang, Xiaoxue
Li, Wenqian
Wang, Ya
Zeng, Shaoqing
Li, Huayi
Chen, Gang
Huang, Xiaoyuan
Ma, Ding
Liu, Dan
Gao, Qinglei
author_sort Tan, Jiahong
collection PubMed
description PARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.
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spelling pubmed-81752372021-06-17 C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer Tan, Jiahong Zheng, Xu Li, Mengchen Ye, Fei Song, Chunyan Xu, Cheng Zhang, Xiaoxue Li, Wenqian Wang, Ya Zeng, Shaoqing Li, Huayi Chen, Gang Huang, Xiaoyuan Ma, Ding Liu, Dan Gao, Qinglei Oncogene Article PARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment. Nature Publishing Group UK 2021-05-08 2021 /pmc/articles/PMC8175237/ /pubmed/33966038 http://dx.doi.org/10.1038/s41388-021-01788-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tan, Jiahong
Zheng, Xu
Li, Mengchen
Ye, Fei
Song, Chunyan
Xu, Cheng
Zhang, Xiaoxue
Li, Wenqian
Wang, Ya
Zeng, Shaoqing
Li, Huayi
Chen, Gang
Huang, Xiaoyuan
Ma, Ding
Liu, Dan
Gao, Qinglei
C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer
title C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer
title_full C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer
title_fullStr C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer
title_full_unstemmed C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer
title_short C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer
title_sort c/ebpβ promotes poly(adp-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175237/
https://www.ncbi.nlm.nih.gov/pubmed/33966038
http://dx.doi.org/10.1038/s41388-021-01788-4
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