Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-06-06 DOI:10.1016/j.xcrm.2025.102192

Sarah Naomi Olsen, Bryn Anderson, Charlie Hatton, Zhengtao Chu, Christopher Simpkins, Yanhe Wen, Wallace Bourgeois, Elena L Haarer, Myles Brown, Rinath Jeselsohn, Alana L Welm, Eneda Toska, Scott A Armstrong

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Abstract

KAT6A is a histone acetyltransferase that is emerging as a therapeutic target in cancer, including estrogen receptor-positive (ER+) breast cancer. Here, we perform CRISPR screens to identify the chromatin adaptor Menin as a regulator of KAT6A/B inhibitor response. Co-treatment with KAT6A/B and Menin inhibitors has synergistic anti-proliferative effects in ER+, but not ER-, breast cancer lines. Our data reveal that KAT6A and Menin-KMT2A cooperatively regulate ER-driven gene expression via direct effects on ESR1 expression and co-localization at ER target genes. Combined KAT6A/B and Menin inhibition displaces KAT6A and Menin-KMT2A from promoters of ER-driven genes leading to selective RNA polymerase II chromatin loss at these loci. Importantly, combined KAT6A/B and Menin inhibition is effective in ER+ patient-derived xenograft models and in multiple models of endocrine resistance. KAT6A/B and Menin inhibitors are currently in clinical trials and have shown manageable toxicity profiles, underscoring the potential therapeutic relevance for ER+ breast cancer.

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联合抑制KAT6A/B和Menin逆转乳腺癌中雌激素受体驱动的基因表达程序。

KAT6A是一种组蛋白乙酰转移酶，正在成为癌症的治疗靶点，包括雌激素受体阳性（ER+）乳腺癌。在这里，我们进行了CRISPR筛选，以鉴定染色质接头Menin作为KAT6A/B抑制剂反应的调节因子。与KAT6A/B和Menin抑制剂联合治疗在ER+而不是ER-乳腺癌细胞系中具有协同抗增殖作用。我们的数据显示，KAT6A和Menin-KMT2A通过直接影响ESR1的表达和ER靶基因的共定位来协同调节ER驱动基因的表达。KAT6A/B和Menin的联合抑制将KAT6A和Menin- kmt2a从er驱动基因的启动子中取代，导致这些位点的选择性RNA聚合酶II染色质丢失。重要的是，KAT6A/B和Menin联合抑制在ER+患者来源的异种移植模型和多种内分泌抵抗模型中是有效的。KAT6A/B和Menin抑制剂目前正在临床试验中，并显示出可控的毒性特征，强调了ER+乳腺癌的潜在治疗相关性。

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 Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.