Skin cancer is the most common type of cancer in the US, with an estimated 3.5 million cases diagnosed each year. Exposure to ultraviolet (UV) radiation, namely UVA (320-400 nm) and UVB (290-320 nm), is the major risk factor for the development of skin cancer. UVA is 20-fold more abundant in sunlight than UVB and is the major component of tanning beds. However, the mechanism of UVA's contribution to skin cancer remains unclear. One putative effector of UVA in skin cancer is p62, a selective autophagy cargo protein and substrate. We have found that UVA upregulates p62 expression, independent of autophagy, by inducing transcription of p62. p62 is upregulated in many types of cancer, including squamous cell carcinoma (SCC) and melanoma, and can facilitate the activation of a number of pathways to promote cell proliferation, invasion, inflammation, and survival. We have previously shown that p62 stabilizes Twist1 to promote invasion and proliferation, indicating p62 can function independent of autophagy to promote tumor progression. However, the function of p62 in UVA-induced tumor progression is unknown. Using a candidate gene approach, we identified a novel interaction between p62 and cyclooxygenase-2 (COX-2), which suggests a putative function for p62 in UVA-induced skin cancer. COX-2 is a prostaglandin synthase often overexpressed in cancer, where it correlates with poor prognosis. COX-2 promotes cell proliferation and survival, and inhibition of COX-2 prevents skin cancer development. COX-2 protein expression is induced concomitantly with p62 in response to UVA and knockdown of p62 prevents induction of COX-2 by UVA. As COX-2 transcription is not induced by UVA in skin cancer cells along with p62, we assessed a possible protein-level regulatory mechanism. Co-immunoprecipitation of endogenous p62 and COX-2 in skin cancer cells reveals a novel physical interaction between these proteins. Therefore, we hypothesize that p62 transcription is induced by UVA to promote stability of cyclooxygenase-2 (COX-2) and consequently, tumor progression. This project aims to further understand how UVA regulates p62 and thus COX-2 availability, and the functional significance for skin tumor progression. As both p62 and COX-2 are critical for skin tumor progression, understanding the link between these proteins will unravel a signaling axis central to skin cancer progression.

Citation Format: Ashley Sample, Lei Qiang, Baozhong Zhao, Yu-Ying He. The role of p62-dependent regulation of COX-2 in UVA response and skin tumor progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4060.