SOX10 ablation arrests cell cycle, induces senescence, and suppresses melanomagenesis.
SOX10 ablation arrests cell cycle, induces senescence, and suppresses melanomagenesis.
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DOI：
10.1158/0008-5472.can-12-4620
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发表时间：
2013-09-15
期刊：
影响因子：
11.2
通讯作者：
Pavan WJ
中科院分区：
文献类型：
--
作者：
Cronin JC;Watkins-Chow DE;Incao A;Hasskamp JH;Schönewolf N;Aoude LG;Hayward NK;Bastian BC;Dummer R;Loftus SK;Pavan WJ
转录因子 SOX10 对于神经嵴细胞谱系的生存和正常分化至关重要，在黑素细胞的生成和维持中发挥着重要作用。 SOX10 在黑色素瘤中也高表达，但其在疾病进展中的作用尚未确定。在这里，我们报告黑色素瘤肿瘤细胞系需要野生型 SOX10 表达才能增殖，而 SOX10 单倍体不足会减少代谢型谷氨酸受体 1 (Grm1Tg) 转基因小鼠模型中黑色素瘤的发生。人黑色素瘤细胞中 SOX10 的稳定敲低可抑制细胞生长、改变细胞形态并诱导衰老。 SOX10 稳定缺失的黑色素瘤细胞被停滞在细胞周期的 G1 期，黑色素细胞决定因子 MITF 表达减少，p21WAF1 和 p27KIP2 表达升高，RB 低磷酸化，其结合伴侣 E2F1 水平降低。由于细胞周期失调是肿瘤转化的核心事件，SOX10 在维持黑色素细胞细胞周期控制中的作用为靶向治疗或预防黑色素瘤提供了合理的新方向。
The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation, and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1Tg) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced expression in the melanocyte determining factor MITF, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB and reduced levels of its binding partner E2F1. Since cell cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma.