Melanoma is the deadliest form of skin cancer and its incidence is rising, creating a costly and significant clinical problem. Exposure to ultraviolet (UV) radiation, namely UVA (315-400 nm) and UVB (280-315 nm), is a major risk factor for melanoma development. Cumulative UV radiation exposure from sunlight or tanning beds contributes to UV-induced DNA damage, oxidative stress, and inflammation in the skin. A number of factors, including hair color, skin type, genetic background, location, and history of tanning, determine the skin's response to UV radiation. In melanocytes, dysregulation of this UV radiation response can lead to melanoma. Given the complex origins of melanoma, it is difficult to develop curative therapies and universally effective preventative strategies. Here, we describe and discuss the mechanisms of UV-induced skin damage responsible for inducing melanomagenesis, and explore options for therapeutic and preventative interventions.

Macroautophagy (hereafter autophagy) is a cellular catabolic process that is essential for maintaining tissue homeostasis and regulating various normal and pathologic processes in human diseases including cancer. One cancer-driving process is accumulation of genetic mutations due to impaired DNA damage repair, including nucleotide excision repair. Here we show that autophagy positively regulates nucleotide excision repair through enhancing DNA damage recognition by the DNA damage sensor proteins XPC and DDB2 via 2 pathways. First, autophagy deficiency downregulates the transcription of XPC through TWIST1-dependent activation of the transcription repressor complex E2F4-RBL2. Second, autophagy deficiency impairs the recruitment of DDB2 to ultraviolet radiation (UV)-induced DNA damage sites through TWIST1-mediated inhibition of EP300. In mice, the pharmacological autophagy inhibitor Spautin-1 promotes UVB-induced tumorigenesis, whereas the autophagy inducer rapamycin reduces UVB-induced tumorigenesis. These findings demonstrate the crucial role of autophagy in maintaining proper nucleotide excision repair in mammalian cells and suggest a previously unrecognized tumor-suppressive mechanism of autophagy in cancer.

Macroautophagy (hereafter autophagy) is a cellular "self-eating" process that is implicated in many human cancers, where it can act to either promote or suppress tumorigenesis. However, the role of autophagy in regulation of inflammation during tumorigenesis remains unclear. Here we show that autophagy is induced in the epidermis by ultraviolet (UV) irradiation and autophagy gene Atg7 promoted UV-induced inflammation and skin tumorigenesis. Atg7 regulated UV-induced cytokine expression and secretion, and promoted Ptgs2/Cox-2 expression through both a CREB1/CREB-dependent cell autonomous mechanism and an IL1B/IL1β-dependent non-cell autonomous mechanism. Adding PGE increased UV-induced skin inflammation and tumorigenesis, reversing the epidermal phenotype in mice with Atg7 deletion in keratinocytes. Similar to ATG7 knockdown in human keratinocytes, ATG5 knockdown inhibited UVB-induced expression of PTGS2 and cytokines. Furthermore, ATG7 loss increased the activation of the AMPK pathway and the phosphorylation of CRTC1, and led to endoplasmic reticulum (ER) accumulation and reduction of ER stress. Inducing ER stress and inhibiting calcium influx into the ER by thapsigargin reverses the inflammation and tumorigenesis phenotype in mice with epidermal Atg7 deletion. Taken together, these findings demonstrate that deleting autophagy gene Atg7 leads to a suppression of carcinogen-induced protumorigenic inflammatory microenvironment and tumorigenesis of the epithelium.

UV radiation exposure from sunlight and artificial tanning beds is the major risk factor for the development of skin cancer and skin photoaging. UV-induced skin damage can trigger a cascade of DNA damage response signaling pathways, including cell cycle arrest, DNA repair, and, if damage is irreparable, apoptosis. Compensatory proliferation replaces the apoptotic cells to maintain skin barrier integrity. Disruption of these processes can be exploited to promote carcinogenesis by allowing the survival and proliferation of damaged cells. UV radiation also induces autophagy, a catabolic process that clears unwanted or damaged proteins, lipids, and organelles. The mechanisms by which autophagy is activated following UV exposure, and the functions of autophagy in UV response are only now being clarified. Here, we summarize the current understanding of the mechanisms governing autophagy regulation by UV, the roles of autophagy in regulating cellular response to UV-induced photodamage, and the implications of autophagy modulation in the treatment and prevention of photoaging and skin cancer.

Edited by George N. DeMartinoMacroautophagy (hereafter autophagy) is a catabolic cellular self-eating process by which unwanted organelles or proteins are delivered to lysosomes for degradation through autophagosomes. Although the role of autophagy in cancer has been shown to be context-dependent, the role of autophagy in tumor cell survival has attracted great interest in targeting autophagy for cancer therapy. One family of potential autophagy blockers is the quinoline-derived antimalarial family, including chloroquine (CQ). However, the molecular basis for tumor cell response to CQ remains poorly understood. We show here that Macroautophagy (hereafter autophagy) is an evolutionarily conserved cellular self-eating process, in which proteins or organelles are delivered to lysosomes for degradation (1, 2). Autophagy can inhibit or promote tumor development depending on the context (3-6). Autophagy deficiency has been reported to increase genome instability induced by oxidative stress or DNA damage, a well known factor for cancer initiation and progression (2,7,8). However, autophagy has been shown to promote cell survival and adaptation by protecting cells against various stress conditions such as anticancer treatment and unfavorable tumor microenvironments such as anoikis, starvation, and hypoxic or oxidative conditions (9, 10). Increasing evidence has indicated that inhibition of autophagy suppresses tumor growth, invasion, and metastasis (11-13). These findings suggest autophagy inhibition as an attractive new strategy to prevent and treat cancer.One of the representative autophagy inhibitors is chloroquine (CQ), 2 a lysosomotropic drug approved by the United States Food and Drug Administration for the prophylactic treatment of malaria (14, 15) and the management of lupus erythematosus and rheumatoid arthritis (16,17). Although it has several side effects such as skin rash, muscle damage, and vision problems (18,19), and an overdose can be lethal (20, 21), CQ has recently attracted considerable attention as an antitumor drug due to the potential biological effects on blocking autophagy in tumor cells (22)(23)(24). However, recent studies have shown that CQ exhibits its antitumor activity independent of autophagy inhibition (25), including normalizing the tumor vasculature (26). Several phase I and II clinical trials with CQ suggest that CQ can moderately improve the clinical activity of radiation therapy and several chemotherapeutics (22)(23)(24). In contrast, another antimalarial quinacrine is shown to induce cancer cell death through autophagy inhibition and p53-dependent inhibition of the oxidative pentose phosphate pathway (27).It is possible that the limited anticancer efficacy of CQ is caused by the induction of resistance pathways in tumor cells. However, how CQ induces resistance is unknown. In this study, we found that CQ induced NF-B activation through autophagosome accumulation, p62, and JNK signaling, which mediated CQ resistance in both squamous cell carcinoma (SCC) and melanoma cells. To determi...

Sirtuins (SIRT1-7) are NAD-dependent proteins with the enzymatic activity of deacetylases and ADP ribosyltransferases. SIRT1 is the proto member of the proteins in the mammalian sirtuin family and plays multiple roles in aging and disease. Using mice with epidermis-specific SIRT1 deletion, we show that SIRT1 is required for efficient wound healing. SIRT1 deficiency in the epidermis inhibited the regeneration of both the epidermis and the dermal stroma. SIRT1 loss altered the production of many cytokines, inhibited the recruitment of macrophages, neutrophils, and mast cells, the recruitment and activation of fibroblasts, and angiogenesis in the granulation tissue. In keratinocytes, SIRT1 knockdown inhibited EMT, cell migration, and TGF-β signaling. For the first time, using skin-specific mouse model, we demonstrate that epidermal SIRT1 plays a crucial role in wound repair. These findings are novel in understanding how wound healing is regulated. Our findings provide in vivo and in vitro evidence that SIRT1 in the epidermis regulates cell migration, redox response, inflammation, epidermis re-epithelialization, granulation formation, and proper wound healing in mice.

Skin cancer is the most common cancer, and exposure to ultraviolet (UV) radiation, namely UVA and UVB, is the major risk factor for skin cancer development. UVA is significantly less effective in causing direct DNA damage than UVB, but UVA has been shown to increase skin cancer risk. The mechanism by which UVA contributes to skin cancer remains unclear. Here, using RNA-Seq, we show that UVA induces autophagy and lysosomal gene expression, including the autophagy receptor and substrate p62. We found that UVA activates transcription factor EB (TFEB), a known regulator of autophagy and lysosomal gene expression, which, in turn, induces transcription. Next, we identified a novel relationship between p62 and cyclooxygenase-2 (COX-2), a prostaglandin synthase critical for skin cancer development. expression was up-regulated by UVA-induced p62, suggesting that p62 plays a role in UVA-induced skin cancer. Moreover, we found that p62 stabilizes COX-2 protein through the p62 ubiquitin-associated domain and that p62 regulates prostaglandin E production 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. Because prostaglandin E is known to promote pro-tumorigenic immune cell infiltration, increase proliferation, and inhibit keratinocyte differentiation , 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.

A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM. A majority of GBM tumors have dysregulated EGFR signaling, due most frequently to EGFR amplification or the presence of a constitutively active EGFRvIII mutant. Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that can activate multiple MAPK pathways. In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR-DOCK180-RAC1-MLK3-JNK signaling axis that drives glioblastoma cell migration and dissemination. On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma. .