Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression.
Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression.
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DOI：
10.1158/0008-5472.can-14-3076
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发表时间：
2015-06-01
期刊：
影响因子：
11.2
通讯作者：
Chang CJ
中科院分区：
文献类型：
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作者：
Chang CC;Wu MJ;Yang JY;Camarillo IG;Chang CJ
肥胖与乳腺癌进展有关，但其潜在机制仍不清楚。在这里，我们报告如何瘦素，肥胖相关的脂肪因子，调节转录途径沉默的遗传程序上皮细胞的稳态在乳腺癌干细胞样细胞（CSC），促进恶性进展。使用全基因组ChIP-seq和RNA表达谱分析，我们确定了活化的STAT 3和G9 a组蛋白甲基转移酶在miR-200 c的表观遗传沉默中的作用，miR-200 c促进了乳腺CSC的形成，其定义为瘦素受体（OBRhi）的细胞表面水平升高。抑制STAT 3/G9 a通路恢复了miR-200 c的表达，这反过来又将CSC表型逆转为更分化的上皮表型。在由饮食诱导的肥胖驱动的乳腺癌大鼠模型中，STAT 3阻断抑制了CSC样OBRhi群体并消除了肿瘤进展。总之，我们的研究结果显示了靶向STAT 3-G9 a信号传导如何在肥胖相关的乳腺癌进展过程中调节CSC可塑性，这表明了一种抑制CSC池和限制乳腺恶性肿瘤的新治疗模式。
Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBRhi). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBRhi population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy.