Abstract
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.
Highlights
Skin cancer is the most commonly diagnosed malignancy in the United States, and the incidence of skin cancer has increased dramatically over the last few decades.[1]
It has been well documented that DNA damage frequently caused by irradiation in keratinocytes and melanocytes plays a crucial role in the initiation and progression of skin cancer in high‐risk individuals 4,5; the relevance of DNA damage responses (DDR) in tumor skin keratinocytes has not been extensively investigated yet
We show that the steady‐state levels of Sam[68] are elevated in the skin tumors derived from human basal cell carcinomas (BCC) and squamous cell carcinomas (SCCs) patients and in skin tumor lesions from genetically manipulated Gli2tg/+ mice
Summary
Skin cancer is the most commonly diagnosed malignancy in the United States, and the incidence of skin cancer has increased dramatically over the last few decades.[1] Nonmelanoma skin cancer (NMSC), which includes squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), is the most common type of skin cancer and is associated with significant morbidity and mortality.[2,3] It has been well documented that DNA damage frequently caused by irradiation in keratinocytes and melanocytes plays a crucial role in the initiation and progression of skin cancer in high‐risk individuals 4,5; the relevance of DNA damage responses (DDR) in tumor skin keratinocytes has not been extensively investigated yet. Our findings reveal a crucial role of Sam[68] in the development and survival of NMSC through regulating multiple signaling pathways in DDR
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