Sam68 is required for the growth and survival of nonmelanoma skin cancer
Sam68 is required for the growth and survival of nonmelanoma skin cancer
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DOI：
10.1002/cam4.2513
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发表时间：
2019-08-22
期刊：
影响因子：
4
通讯作者：
Wan, Fengyi
中科院分区：
文献类型：
--
作者：
Fu, Kai;Sun, Xin;Wan, Fengyi
尽管靶向 DNA 修复信号通路已成为皮肤癌的一种有前途的治疗方法，但 DNA 损伤反应 (DDR) 在最常见的皮肤癌类型非黑色素瘤皮肤癌 (NMSC) 的发展和生存中的相关性仍然不清楚。在这里，我们报道了 68 kDa (Sam68) 有丝分裂期间的 Src 相关底物（DDR 中的一种早期信号分子）在 NMSC 患者的皮肤肿瘤组织和 Gli2 转基因小鼠的皮肤病变中升高。 Sam68 的下调会影响人类肿瘤角质形成细胞的生长和存活，Sam68 的基因消融可延迟 Gli2 转基因小鼠的基底细胞癌 (BCC) 的发病。此外，Sam68 在 DNA 损伤诱导的 DNA 修复和角质形成细胞中的核因子 kappa B (NF-kappa B) 信号通路中发挥着关键作用，从而赋予角质形成细胞对 DNA 损伤剂的敏感性。总之，我们的数据揭示了 Sam68 在调节角质形成细胞 DDR 中的新功能，这对于 NMSC 的生长和存活至关重要。
Although targeting DNA repair signaling pathways has emerged as a promising therapeutic for skin cancer, the relevance of DNA damage responses (DDR) in the development and survival of nonmelanoma skin cancer (NMSC), the most common type of skin cancer, remains obscure. Here, we report that Src-associated substrate during mitosis of 68 kDa (Sam68), an early signaling molecule in DDR, is elevated in skin tumor tissues derived from NMSC patients and skin lesions from Gli2-transgenic mice. Downregulation of Sam68 impacts the growth and survival of human tumor keratinocytes and genetic ablation of Sam68 delays the onset of basal cell carcinomas (BCC) in Gli2-transgenic mice. Moreover, Sam68 plays a critical role in DNA damage-induced DNA repair and nuclear factor kappa B (NF-kappa B) signaling pathways in keratinocytes, hence conferring keratinocyte sensitivity to DNA damaging agents. Together, our data reveal a novel function of Sam68 in regulating DDR in keratinocytes that is crucial for the growth and survival of NMSC.