Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cancer Med. 2019 Oct;8(13):6106-6113. doi: 10.1002/cam4.2513. Epub 2019 Aug 22.
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-κB) 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.
尽管靶向 DNA 修复信号通路已成为治疗皮肤癌的一种有前途的方法，但在最常见的皮肤癌——非黑色素瘤皮肤癌（NMSC）的发生和存活中，DNA 损伤反应（DDR）的相关性仍然不清楚。在这里，我们报告说，Src 相关底物在有丝分裂中 68 kDa（Sam68），DDR 中的早期信号分子，在源自 NMSC 患者的皮肤肿瘤组织和 Gli2 转基因小鼠的皮肤损伤中升高。Sam68 的下调会影响人肿瘤角质形成细胞的生长和存活，并且 Sam68 的遗传缺失会延迟 Gli2 转基因小鼠基底细胞癌（BCC）的发生。此外，Sam68 在角质形成细胞中的 DNA 损伤诱导的 DNA 修复和核因子 kappa B（NF-κB）信号通路中发挥关键作用，从而使角质形成细胞对 DNA 损伤剂敏感。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。
