ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer.

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-11-20 DOI:10.1016/j.celrep.2024.114991

Benedetto DiCiaccio, Marco Seehawer, Zheqi Li, Andriana Patmanidis, Triet Bui, Pierre Foidart, Jun Nishida, Clive S D'Santos, Evangelia K Papachristou, Malvina Papanastasiou, Andrew H Reiter, Xintao Qiu, Rong Li, Yijia Jiang, Xiao-Yun Huang, Anton Simeonov, Stephen C Kales, Ganesha Rai, Madhu Lal-Nag, Ajit Jadhav, Myles Brown, Jason S Carroll, Henry W Long, Kornelia Polyak

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Abstract

We previously described that the KDM5B histone H3 lysine 4 demethylase is an oncogene in estrogen-receptor-positive breast cancer. Here, we report that KDM5A is amplified and overexpressed in basal breast tumors, and KDM5 inhibition (KDM5i) suppresses the growth of KDM5-amplified breast cancer cell lines. Using CRISPR knockout screens in a basal breast cancer cell line with or without KDM5i, we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitizes cells to KDM5i, whereas deletion of RHO-GTPases leads to resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed co-localization of ZBTB7A and KDM5A/B at promoters with high histone H3K4me3 and dependence of KDM5A chromatin binding on ZBTB7A. ZBTB7A knockout altered the transcriptional response to KDM5i at NF-κB targets and mitochondrion-related pathways. High expression of ZBTB7A in triple-negative breast cancer is significantly associated with poor response to neoadjuvant chemotherapy. Our work furthers the understanding of KDM5-mediated gene regulation and identifies mediators of sensitivity to KDM5i.

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ZBTB7A 是基底乳腺癌中 KDM5 驱动的转录网络的调节器。

我们以前曾描述过 KDM5B 组蛋白 H3 赖氨酸 4 去甲基化酶是雌激素受体阳性乳腺癌的致癌基因。在这里，我们报告了 KDM5A 在基底乳腺肿瘤中的扩增和过表达，KDM5 抑制剂（KDM5i）能抑制 KDM5 扩增的乳腺癌细胞系的生长。通过在含有或不含 KDM5i 的基底乳腺癌细胞系中进行 CRISPR 基因敲除筛选，我们发现 ZBTB7A 转录因子和核心 SAGA 复合物的缺失会使细胞对 KDM5i 敏感，而 RHO-GTPases 的缺失则会导致抗性。染色质免疫沉淀测序（ChIP-seq）和 RNA 测序（RNA-seq）显示，ZBTB7A 和 KDM5A/B 共同定位在组蛋白 H3K4me3 高的启动子上，KDM5A 染色质结合依赖于 ZBTB7A。ZBTB7A 基因敲除改变了 NF-κB 靶点和线粒体相关通路对 KDM5i 的转录反应。ZBTB7A在三阴性乳腺癌中的高表达与新辅助化疗的不良反应密切相关。我们的研究进一步加深了对KDM5介导的基因调控的理解，并确定了对KDM5i敏感的介质。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.