Pei Jing, Zhang ShengQuan, Yang Xiaowei, Han Chunguang, Pan Yubo, Li Jun, Wang Zhaorui, Sun Chenyu, Zhang Jing
Department of Breast Surgery, First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, Anhui 230022, PR China.
Department of Biochemistry and Molecular Biology, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, PR China.
Transl Oncol. 2023 Feb;28:101615. doi: 10.1016/j.tranon.2022.101615. Epub 2022 Dec 31.
Altered epigenetic reprogramming and events contribute to breast cancer (Bca) progression and metastasis. How the epigenetic histone demethylases modulate breast cancer progression remains poorly defined. We aimed to elucidate the biological roles of KDM4A in driving Notch1 activation and Bca progression.
The KDM4A expression in Bca specimens was analyzed using quantitative PCR and immunohistochemical assays. The biological roles of KDM4A were evaluated using wound-healing assays and an in vivo metastasis model. The Chromatin Immunoprecipitation (ChIP)-qPCR assay was used to determine the role of KDM4A in Notch1 regulation.
Here, we screened that targeting KDM4A could induce notable cell growth suppression. KDM4A is required for the growth and progression of Bca cells. High KDM4A enhances tumor migration abilities and in vivo lung metastasis. Bioinformatic analysis suggested that KDM4A was highly expressed in tumors and high KDM4A correlates with poor survival outcomes. KDM4A activates Notch1 expressions via directly binding to the promoters and demethylating H3K9me3 modifications. KDM4A inhibition reduces expressions of a list of Notch1 downstream targets, and ectopic expressions of ICN1 could restore the corresponding levels. KDM4A relies on Notch1 signaling to maintain cell growth, migration and self-renewal capacities. Lastly, we divided a panel of cell lines into KDM4A and KDM4A groups. Targeting Notch1 using specific LY3039478 could efficiently suppress cell growth and colony formation abilities of KDM4A Bca.
Taken together, KDM4A could drive Bca progression via triggering the activation of Notch1 pathway by decreasing H3K9me3 levels, highlighting a promising therapeutic target for Bca.
表观遗传重编程的改变及相关事件促进乳腺癌（Bca）的进展和转移。表观遗传组蛋白去甲基化酶如何调节乳腺癌进展仍不清楚。我们旨在阐明KDM4A在驱动Notch1激活和Bca进展中的生物学作用。
采用定量PCR和免疫组化分析Bca标本中KDM4A的表达。使用伤口愈合试验和体内转移模型评估KDM4A的生物学作用。染色质免疫沉淀（ChIP）-qPCR试验用于确定KDM4A在Notch1调控中的作用。
在此，我们筛选出靶向KDM4A可显著抑制细胞生长。KDM4A是Bca细胞生长和进展所必需的。高表达的KDM4A增强肿瘤迁移能力和体内肺转移。生物信息学分析表明，KDM4A在肿瘤中高表达，且高KDM4A与不良生存结果相关。KDM4A通过直接结合启动子并去甲基化H3K9me3修饰来激活Notch1表达。抑制KDM4A可降低一系列Notch1下游靶点的表达，异位表达ICN1可恢复相应水平。KDM4A依赖Notch1信号维持细胞生长、迁移和自我更新能力。最后，我们将一组细胞系分为KDM4A和KDM4A组。使用特异性LY3039478靶向Notch1可有效抑制KDM4A Bca的细胞生长和集落形成能力。
综上所述，KDM4A可通过降低H3K9me3水平触发Notch1通路激活来驱动Bca进展，凸显了其作为Bca有前景的治疗靶点。
