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7 Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)

7 Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)

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Chapter 12



Sirtuins and Stress Response in Skin

Cancer, Aging, and Barrier Function

Yu-Ying He



Abstract Sirtuins (SIRT1-7) are mammalian counterparts of the yeast silent

information regulator 2 (Sir2) and are a family of NAD-dependent protein

deacetylases and ADP ribosyltransferases. Sirtuins regulate numerous pathways in

metabolism, aging and cancer. They are critical modulators in the cellular response

to metabolic, oxidative, or genotoxic stress. Recent advances have demonstrated the

pivotal role of sirtuin proteins in aging and a wide range of diseases including

cancer in many organs. Skin is the essential barrier protecting organisms against

environmental insults and minimizing water loss from the body. New evidence in

mouse models and in vitro systems has illustrated that sirtuins have important roles

in skin physiology, in the barrier function, aging, and diseases such as skin cancer.

This review summarizes recent advances in understanding how sirtuins regulate the

skin stress response in skin cancer, aging, and barrier integrity at the molecular,

cellular, and organismal levels, and in how modulating sirtuins may help prevent or

treat skin cancer, skin barrier defects, and other skin diseases.



Á



Á



Á



Á



Á



Keywords Sirtuins SIRT1 SIRT2 SIRT3 SIRT6 skin cancer Skin aging

Skin barrier UV DNA repair



Á



12.1



Á



Á



Introduction and Overview on Sirtuins



Sirtuins (SIRT1-7) are NAD-dependent proteins with the enzymatic activity of

deacetylases and ADP ribosyltransferases (Blander and Guarente 2004; Haigis and

Guarente 2006; Haigis and Sinclair 2010; Michan and Sinclair 2007; Saunders and

Verdin 2007). They are mammalian counterparts of the yeast silent information

regulator 2 (Sir2). Since SIRT1 was first discovered about 15 years ago, there have

been major breakthroughs in understanding the critical roles of sirtuins in

Y.-Y. He (&)

Department of Medicine, Section of Dermatology, University of Chicago,

5841 S Maryland Ave, MC 5067, Chicago, IL 60637, USA

e-mail: yyhe@medicine.bsd.uchicago.edu

© Springer International Publishing Switzerland 2016

G.T. Wondrak (ed.), Skin Stress Response Pathways,

DOI 10.1007/978-3-319-43157-4_12



251



252



Y.-Y. He



Survival



DNA repair



Telomeres



Sirtuins

SIRT1-7



Metabolism

Stem cells



Inflammation



Differentiation



Fig. 12.1 Sirtuins regulates numerous cellular functions in stress response and homeostasis



physiology and pathology (Blander and Guarente 2004; Haigis and Guarente 2006;

Haigis and Sinclair 2010; Michan and Sinclair 2007; Saunders and Verdin 2007).

Sirtuins regulate a wide variety of proteins in the nucleus, cytosol and mitochondria. They are crucial regulators of tissue homeostasis and adaptation under

metabolic, oxidative, or genotoxic stress. Using animal models, recent advances

have demonstrated the illuminating roles of sirtuins in DNA repair, telomere

integrity, metabolism, survival, inflammation, cell differentiation and stem cell

biology in many human diseases including cancer and age-related diseases (Blander

and Guarente 2004; Chalkiadaki and Guarente 2015; Haigis and Guarente 2006;

Haigis and Sinclair 2010; Michan and Sinclair 2007; Saunders and Verdin 2007;

Sebastian and Mostoslavsky 2015) (Fig. 12.1). Based on the molecular and cellular

targets identified, sirtuins are considered to have important roles in skin cancer and

age-related skin diseases (Serravallo et al. 2013). Indeed, using mouse models and

in vitro systems, recent studies have illustrated critical roles of sirtuin proteins in the

skin stress response, homeostasis, and skin diseases. This review focuses on recent

advances in understanding the important roles of sirtuins at the molecular, cellular

and organismal levels in the skin stress response and their function in skin cancer,

aging, and barrier integrity.



12.2



Sirtuins in Skin Cancer



Skin cancer is the most common cancer in the US. In 2012, more than 5.4 million

cases of nonmelanoma skin cancer were treated in over 3.3 million people (Rogers

et al. 2015). The incidence of skin cancer continues to rise at an alarming rate. The

average annual number of adults treated for skin cancer increased from 3.4 million

in 2002–2006 to 4.9 million in 2007–2011 (Guy et al. 2015). Both genetic alterations and environmental risk factors play important roles in the pathogenesis of all

three types of skin cancer—basal cell carcinoma, squamous cell carcinoma, and



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Sirtuins and Stress Response in Skin Cancer and Aging



253



melanoma. In particular, important genetic alterations may be oncogenic or tumor

suppressive; these may increase cell survival and proliferation, impair DNA repair

and checkpoint activation, and induce inflammation in vivo (Bowden 2004; Cleaver

2005; Sundaresan et al. 2012). Targeting these molecular pathways has been

demonstrated to hold promise for skin cancer prevention (Bowden 2004; Ratushny

et al. 2012).



12.2.1 SIRT1 Has a Dual Role in Skin Cancer

Sirtuin 1 (SIRT1) is a proto member of the mammalian sirtuin family. It has been

revealed that SIRT1 regulates various pathways in metabolism, aging, and cancer

(Avivar-Valderas et al. 2011; Blander and Guarente 2004; Chalkiadaki and

Guarente 2015; Haigis and Guarente 2006; Haigis and Sinclair 2010; Michan and

Sinclair 2007; Saunders and Verdin 2007). Over the past decade, SIRT1 has

attracted enormous attention due to its beneficial role in cell metabolism and survival in in vitro and in vivo animal studies (Avivar-Valderas et al. 2011; Blander

and Guarente 2004; Chalkiadaki and Guarente 2015; Haigis and Guarente 2006;

Haigis and Sinclair 2010; Michan and Sinclair 2007; Saunders and Verdin 2007).

Both histone and non-histone targets of SIRT1 have been identified, including

FOXO, p53, PGC-1a, NF-jB, and PPARc (Blander and Guarente 2004; Brooks

and Gu 2009; Michan and Sinclair 2007). Accumulating evidence suggests that the

role of SIRT1 in cancer is complex. It remains under debate whether SIRT1 acts as

a tumor suppressor or as an oncogene in many cancers (Brooks and Gu 2009; Deng

2009; Haigis and Sinclair 2010).

In skin cancer, ultraviolet radiation (UV) serves as the major risk factor by

causing damage to the DNA and other molecules in the cells. By promoting

deacetylation of xeroderma pigmentosum protein A (XPA) (Fan and Luo 2010) and

promoting the expression of xeroderma pigmentosum C (XPC) (Ming et al. 2010),

SIRT1 promotes nucleotide excision repair, which removes UV-induced DNA

damage (Fig. 12.2). In addition, SIRT1 is down-regulated in UV-associated human

skin cancers from Caucasian patients (who are at highest risk) (Ming et al. 2010),

suggesting that in these cancers it is a tumor suppressor. In addition, UV radiation

down-regulates SIRT1, and inhibiting SIRT1 increases p53 acetylation (Cao et al.

2009). The small molecule in grapes, a SIRT1 activator called resveratrol, reduces

skin cancer development in mice treated with UVB radiation or chemical carcinogens (Aziz et al. 2005; Boily et al. 2009). Interestingly, the chemopreventive

effect of resveratrol seems to depend on SIRT1 (Boily et al. 2009).

To elucidate the precise function of SIRT1 in cancer development in vivo, we

have created mice with a keratinocyte-specific SIRT1 deletion and monitored tumor

development following chronic UVB irradiation. Partial loss of SIRT1 increases

UVB-induced tumorigenesis, while complete loss of SIRT1 decreases UV-induced



254



Y.-Y. He



UVB

radiation



Keratin 19

Keratin 15



SIRT6



SIRT1



SIRT2



XPA deacetylation

XPC expression



p53

acetylation



AMPK



AKT



COX-2



Differentiation



Stemness



DNA repair Survival



Survival

Inflammation



Skin tumorigenesis



Differentiation



Melanoma



Fig. 12.2 SIRT1, SIRT2, and SIRT6 regulate DNA repair, survival, differentiation, and

inflammation during tumorigenesis and each has distinct roles in skin tumorigenesis and cancer

pathology



tumorigenesis, which is consistent with its role in promoting UVB-induced DNA

damage repair and suppressing UVB-induced p53-mediated apoptosis (Ming et al.

2015a) (Fig. 12.2). These findings support a gene-dose-dependent role of SIRT1 in

skin cancer in mice.



12.2.2 SIRT1 Is Oncogenic in Melanoma Cells

In addition to non-melanoma skin cancer, SIRT1 also plays an important role in

melanoma. SIRT1 is found to be overexpressed in human melanoma and its small

molecule inhibition imparts an anti-proliferative response via p53 activation

(Wilking et al. 2014) (Fig. 12.2). SIRT1 regulates the level of many proteins,

including p53 target genes (Singh et al. 2014; Wilking et al. 2014). In melanoma

cells SIRT1 is regulated by the transcription factor MITF and promotes melanoma

cell growth and survival (Ohanna et al. 2014). These studies indicate that SIRT1 has

an oncogenic role, and inhibiting SIRT1 may improve anti-melanoma therapy.



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255



12.2.3 SIRT2 Is a Tumor Suppressor in Skin

SIRT2 is a member of the mammalian sirtuin family. As compared with other

sirtuins, SIRT2 is localized primarily in the cytoplasm. It regulates multiple

physiological processes by deacetylating several proteins, including alpha-tubulin

(North et al. 2003) and FOXO1 (Jing et al. 2007); it also deacetylates histone H4 at

lysine 16 (Vaquero et al. 2006). In addition, SIRT2 modulates the mitotic deposition of H4K20 methylation and suppresses skin tumorigenesis (Serrano et al.

2013) (Fig. 12.2). SIRT2 also plays an important role in other cancers. In gliomas,

melanomas, and gastric carcinomas, SIRT2 protein and RNA levels are decreased

(de Oliveira et al. 2012). Using mice with SIRT2 ablation, we have shown that

SIRT2 suppresses skin tumorigenesis, and suggest that SIRT2 promotes keratinocyte differentiation and suppresses tumor cell stemness in association with

down-regulating keratin 19 (Ming et al. 2014b). Knockdown of SIRT2 increased

the level of K19, but did not affect UVB-induced DNA damage repair and apoptosis. K19 has been considered to be a putative marker for epidermal stem cells in

the hair follicle bulge (Michel et al. 1996). As loss of differentiation is known to

promote tumorigenesis (Aymard et al. 2011; Kim et al. 2012), our data indicate that

inhibition of SIRT2 may promote tumor growth in skin through inhibition of differentiation and increasing stemness (Ming et al. 2014b; Wang et al. 2014)

(Fig. 12.2).



12.2.4 SIRT6 Is an Oncogene in Skin

SIRT6 is a member of the sirtuin family and an anti-aging protein important for

many aspects of organismal health (Lombard et al. 2008; Sebastian et al. 2012a;

Tennen and Chua 2011). At the molecular and cellular level, SIRT6 regulates

multiple molecular pathways to modulate gene transcription, glucose homeostasis,

DNA repair, and telomere integrity (Lombard et al. 2008; Sebastian et al. 2012a;

Tennen and Chua 2011). As a positive regulator of genomic integrity, SIRT6 is

predicted to act as a tumor suppressor. Indeed, it is found to suppress tumorigenesis

in the intestine and liver in mice (Marquardt et al. 2013; Min et al. 2012; Sebastian

et al. 2012b). However, a recent study showed that SIRT6 promotes transforming

growth factor-b1 (TGF-b1)/H2O2/HOCl-mediated enhancement of hepatocellular

carcinoma cell tumorigenicity by suppressing cellular senescence (Feng et al.

2015). TGF-b1/H2O2/HOCl up-regulates SIRT6 to inhibit cellular senescence

(Feng et al. 2015). In addition, SIRT6 has been implicated as an oncogene in skin

cancer (Lefort et al. 2013) and prostate cancer (Liu et al. 2013). It seems that its

function may be tissue- and context-dependent.

Using mice with skin-specific SIRT6 ablation, we found that skin-specific

SIRT6 deletion inhibits skin tumorigenesis. SIRT6 promotes the expression of the

pro-inflammatory and pro-survival protein COX-2 through suppressing AMPK



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signaling, an energy-sensing pathway, and increases cell survival and proliferation

(Ming et al. 2014a) (Fig. 12.2). UVB induces SIRT6 expression through activating

the AKT pathway. SIRT6 is up-regulated in human squamous cell carcinoma (Ming

et al. 2014a). SIRT6 also inhibits keratinocyte differentiation and is suppressed by

microRNA-34a, which can also promote skin tumorigenesis (Lefort et al. 2013)

(Fig. 12.2). These findings demonstrate that SIRT6 is an oncogene in skin.



12.3



Sirtuins in Skin Aging



Sirtuins have been shown to reduce the aging process in a broad range of organisms

including mammals (Guarente 2013). Sirtuin activation can inhibit the progression

of aging diseases, including neurodegeneration, diabetes, cardiovascular diseases

and many types of cancer (Guarente 2013; Haigis and Sinclair 2010).



12.3.1 SIRT1 in Skin Aging

Using transgenic mice moderately overexpressing SIRT1 under its own regulatory

elements (Sirt1-tg), a recent study showed that old Sirt1-tg mice present lower

levels of DNA damage, decreased expression of the ageing-associated gene

p16Ink4a, better general health, and fewer spontaneous carcinomas and sarcomas.

Sirt1-tg mice show improved wound healing, providing direct proof of the

anti-aging activity of SIRT1 in mammalian skin and other tissues (Herranz et al.

2010) (Fig. 12.3). Loss of SIRT1 accelerates retinoic acid-induced embryonic stem

cell differentiation by increasing CRABPII acetylation and thus cellular retinoic

acid signaling (Tang et al. 2014). It is possible that SIRT1 is critical for adult stem

cell maintenance in the skin as well. SIRT1 is down-regulated in later passage

fibroblasts (Kim et al. 2015). In dermal fibroblasts, SIRT1 suppresses the expression of matrix metalloproteinases 1 and 3 (MMP1 and MMP3) under basal conditions or exposure to interleukin 1beta (Ohguchi et al. 2010) (Fig. 12.3),

suggesting that SIRT1 inhibits the aging process in the dermis at the basal level and

under inflammation conditions and that agents targeting SIRT1 may reduce the

production of MMPs and thereby slow down the skin aging process.



12.3.2 SIRT6 Has a Potential Role in Skin Aging

SIRT6 regulates various molecular pathways in genomic stability, metabolism, and

aging. SIRT6 knockout mice have displayed genomic instability and several phenotypes of accelerated premature aging (Mostoslavsky et al. 2006). Overexpressing

SIRT6 extends lifespans in male mice but not in female mice (Kanfi et al. 2012).



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