HMGN5 Escorts Oncogenic STAT3 Signaling by Regulating the Chromatin Landscape in Breast Cancer Tumorigenesis
HMGN5 Escorts Oncogenic STAT3 Signaling by Regulating the Chromatin Landscape in Breast Cancer Tumorigenesis
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DOI：
10.1158/1541-7786.mcr-22-0241
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发表时间：
2022-12-01
影响因子：
5.2
通讯作者：
Ren，Jin
中科院分区：
文献类型：
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作者：
Mou，Jiahui;Huang，Meijun;Ren，Jin
癌症进展高度依赖于癌细胞肿瘤形成的能力，其中表观遗传调节发挥着重要作用。然而，促进乳腺肿瘤形成的表观遗传因素却鲜为人知。从三维（3D）球肿瘤形成模型中筛选，调节染色质结构的HMGN5成为乳腺癌的候选治疗靶点，尽管其作用尚不清楚。 HMGN5 在乳腺癌细胞和临床肿瘤的 3D 球体中高表达，也是患者的不利预后标志物。此外，HMGN5在体外和体内控制乳腺癌细胞的肿瘤形成和转移。从机制上讲，HMGN5 在转录上受活性 STAT3 的控制，并进一步护送 STAT3 塑造致癌染色质景观和转录程序。更重要的是，纳米载体包装的 siRNA 干扰 HMGN5 可有效抑制乳腺癌细胞来源的异种移植小鼠模型中的肿瘤生长。意义我们的研究结果揭示了 HMGN5 和 STAT3 之间促进乳腺癌肿瘤发生的新型前馈回路，并表明 HMGN5 作为 STAT3 过度活跃乳腺癌的新型表观遗传治疗靶点。
Cancer progression is highly dependent on the ability of cancer cell tumor formation, in which epigenetic modulation plays an essential role. However, the epigenetic factors promoting breast tumor formation are less known. Screened from three-dimensional (3D)-sphere tumor formation model, HMGN5 that regulates chromatin structures became the candidate therapeutic target in breast cancer, though its role is obscure. HMGN5 is highly expressed in 3D-spheres of breast cancer cells and clinical tumors, also an unfavorable prognostic marker in patients. Furthermore, HMGN5 controls tumor formation and metastasis of breast cancer cellsin vitroandin vivo. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape the oncogenic chromatin landscape and transcriptional program. More importantly, interference of HMGN5 by nanovehicle-packaged siRNA effectively inhibits tumor growth in breast cancer cell–derived xenograft mice model.ImplicationsOur findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic target in STAT3-hyperactive breast cancer.