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Abstract

Skin cancer is the most common form of cancer, representing 40-50% of all cancers diagnosed. Exposure to ultraviolet (UV) radiation, namely UVA (315-400nm) and UVB (280-315nm) is the major risk factor for skin cancer development. Of these, UVA is more abundant,in both sunlight and tanning beds. UVA is significantly less effective in causing direct DNA damage than UVB, but UVA has been shown to increase skin cancer risk through producing reactive oxygen species (ROS). However, the mechanism by which UVA contributes to skin cancer progression remains unclear. Autophagy adaptor protein p62 is a known oncogene and signaling hub. We and others have shown that p62 is up-regulated in melanoma and squamous cell carcinoma (SCC) and that this up-regulation correlates with poor prognosis. Here, we show that UVA induces p62 in both melanocytes and keratinocytes by different mechanisms. In melanocytes and melanoma cells, p62 is up-regulated by UVA in an Nrf2- and ROS-dependent manner. We also identified a novel regulatory feedback loop between p62 and PTEN in melanoma cells. In keratinocytes, however, UVA activates the transcription factor EB (TFEB), a known regulator of autophagy and lysosomal gene expression, to induce p62 transcription. Next, we identified a novel link between p62 and cyclooxygenase-2 (COX-2) in SCC cells. COX-2 expression was up-regulated by UVA-induced p62 in SCC cells, suggesting that p62 plays a role in UVA-induced SCC. Moreover, we found that p62 stabilizes COX-2 protein through the p62 ubiquitin-associated domain and that p62 regulates prostaglandin E2 (PGE2) production in vitro. In a syngeneic squamous cell carcinoma mouse model, p62 knockdown inhibited tumor growth and metastasis. Furthermore, p62-deficient tumors exhibited reduced immune cell infiltration and increased cell differentiation. As PGE2 is known to promote pro-tumorigenic immune cell infiltration, increase proliferation, and inhibit keratinocyte differentiation in vivo, this work suggests that UVA-induced p62 acts through COX-2 to promote skin tumor growth and progression. These findings expand our understanding of UVA-induced skin tumorigenesis and tumor progression and suggest that targeting p62 can help prevent or treat UVA-associated skin cancer.

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