Dual role of SIRT1 in UVB-induced skin tumorigenesis

Ming, Mei; Soltani, Keyoumars; Shea, Christopher R.; Li, Xiaoling; He, Yu‐Ying

doi:10.1038/onc.2013.583

Cited by 49 publications

(49 citation statements)

References 43 publications

(67 reference statements)

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“…Sirtuins have been investigated in cancer pathogenesis (39). SIRT1 is both tumor-suppressive and oncogenic depending on the context and gene dose (39–42). In contrast, SIRT2 is reported to be a tumor suppressor in mice and be down-regulated in human skin cancer (43, 44).…”

Section: Discussionmentioning

confidence: 99%

SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

et al. 2014

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SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival and in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

et al. 2014

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“…18 Briefly, cells were collected at different time points post-UV and DNA was isolated using a QIAamp DNA Mini Kit (Qiagen, 51304). The DNA concentration was calculated from the absorbance at 260 nm using NanoDrop 1000 (NanoDrop products, Wilmington, DE).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial dysfunction activates the AMPK signaling and autophagy to promote cell survival

et al. 2016

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Autophagy is a cellular self-eating process essential for stress response and maintaining tissue homeostasis by lysosomal degradation of unwanted or damaged proteins and organelles. Here, we show that cells with defective mitochondria induce autophagy to promote cell survival through activating the AMPK pathway. Loss of mitochondrial complex III protein cytochrome b activates the AMPK signaling and induced autophagy. Inhibiting mitochondria energetics by mitochondria-targeted agents activates the AMPK signaling and induced autophagy. Genetic inhibition of AMPK inhibits autophagy induction in cells with defective mitochondria, while genetic inhibition of autophagy has no effect on AMPK activation. Mitochondria dysfunction has no effect of DNA repair of UV-induced DNA damage. However, mitochondria dysfunction sensitizes cells to apoptosis induced by UV radiation. Genetic inhibition of autophagy or AMPK sensitized cells to apoptosis in cells with defective mitochondria. Our results demonstrate that AMPK and autophagy senses mitochondria dysfunction and serves as a mechanism for survival. Our findings may provide new insights into the interplay between mitochondria function and autophagy process in maintaining tissue homeostasis, and suggest that this interaction may play important roles in diseases such as cancer and neurodegeneration.

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“…SIRT1 also deacetylates XPA to regulate UV-induced DNA damage repair (21). We have demonstrated previously that SIRT1 positively regulates UV-induced DNA damage repair by promoting XPC expression, and that it has a critical role in skin tumorigenesis and homeostasis (22, 23). In addition, SIRT1 has been found to promote differentiation of normal human keratinocytes in vitro (24), suggesting a possible role in barrier function and thus the development of AD.…”

Section: Introductionmentioning

confidence: 99%

Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge

Ming

Zhao

Shea

et al. 2015

Journal of Allergy and Clinical Immunology

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Background Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin. Mutational loss of the skin barrier protein filaggrin predisposes individuals to the development of atopic dermatitis (AD). Objective to determine the role of SIRT1 in skin barrier function, filaggrin expression, and the development of AD. Methods Skin histology of mice with skin-specific SIRT1 deletion and wild-type controls was examined by Hematoxyline and Eosin (H&E). Protein and mRNA abundance was analyzed by immunoblot, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by ELISA. Results Here we show that filaggrin is regulated by the protein deacetylase SIRT1, and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD-like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin, SIRT1 knockdown or genetic deletion down-regulates filaggrin, and regulation of filaggrin expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes the activation of the aryl hydrocarbon receptor (AhR), and the AhR ligand restores filaggrin expression in SIRT1-inhibited cells. As compared with normal human skin, SIRT1 is down-regulated in the lesions of atopic dermatitis as well as non-atopic dermatitis. Conclusion Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacological target, and may facilitate the development of mechanism-based agents for AD prevention and therapy.

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Dual role of SIRT1 in UVB-induced skin tumorigenesis

Cited by 49 publications

References 43 publications

SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

Mitochondrial dysfunction activates the AMPK signaling and autophagy to promote cell survival

Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge

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