TY - JOUR
T1 - Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma
AU - George, Jasmine
AU - Nihal, Minakshi
AU - Singh, Chandra K.
AU - Zhong, Weixiong
AU - Liu, Xiaoqi
AU - Ahmad, Nihal
N1 - Publisher Copyright:
© 2015 The Authors
PY - 2016
Y1 - 2016
N2 - Melanoma, the most aggressive form of skin cancer, is often fatal if not treated early. Therefore, novel target-based strategies are required to combat this neoplasm. The objective of this study was to determine the role and functional significance of the mitochondrial sirtuin 3 (SIRT3) in melanoma. We found that compared with normal primary and immortalized human melanocytes, SIRT3 is significantly overexpressed in multiple human melanoma cells at mRNA and protein levels. Further, employing human tissue microarray, we found that SIRT3 is significantly upregulated in clinical melanoma tissues, compared with melanocytic nevi tissues. Furthermore, a short hairpin RNA-mediated knockdown of SIRT3 in human melanoma cells resulted in (i) a decrease in cellular proliferation, colony formation, and cellular migration; (ii) induction of senescence as shown by an increase in senescence-associated beta-galactosidase activity and formation of senescence-associated heterochromatin foci as well as an increase in mRNA and protein levels of p16INK4a and p21Waf1; (iii) G1-phase arrest of the cell cycle; and (iv) decreases in mRNA and protein levels of cyclins (D1, E1) and cyclin-dependent kinases (2, 4, and 6). Conversely, forced exogenous overexpression of SIRT3 promoted an increase in proliferative potential of Hs294T melanoma cells and normal immortalized Mel-ST melanocytes. Finally, we found that SIRT3 knockdown significantly inhibited tumorigenesis in a xenograft model in vivo. To our knowledge, this is the first study supporting the pro-proliferative function of SIRT3 in melanoma.
AB - Melanoma, the most aggressive form of skin cancer, is often fatal if not treated early. Therefore, novel target-based strategies are required to combat this neoplasm. The objective of this study was to determine the role and functional significance of the mitochondrial sirtuin 3 (SIRT3) in melanoma. We found that compared with normal primary and immortalized human melanocytes, SIRT3 is significantly overexpressed in multiple human melanoma cells at mRNA and protein levels. Further, employing human tissue microarray, we found that SIRT3 is significantly upregulated in clinical melanoma tissues, compared with melanocytic nevi tissues. Furthermore, a short hairpin RNA-mediated knockdown of SIRT3 in human melanoma cells resulted in (i) a decrease in cellular proliferation, colony formation, and cellular migration; (ii) induction of senescence as shown by an increase in senescence-associated beta-galactosidase activity and formation of senescence-associated heterochromatin foci as well as an increase in mRNA and protein levels of p16INK4a and p21Waf1; (iii) G1-phase arrest of the cell cycle; and (iv) decreases in mRNA and protein levels of cyclins (D1, E1) and cyclin-dependent kinases (2, 4, and 6). Conversely, forced exogenous overexpression of SIRT3 promoted an increase in proliferative potential of Hs294T melanoma cells and normal immortalized Mel-ST melanocytes. Finally, we found that SIRT3 knockdown significantly inhibited tumorigenesis in a xenograft model in vivo. To our knowledge, this is the first study supporting the pro-proliferative function of SIRT3 in melanoma.
UR - http://www.scopus.com/inward/record.url?scp=84978110953&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978110953&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2015.12.026
DO - 10.1016/j.jid.2015.12.026
M3 - Article
C2 - 26743598
AN - SCOPUS:84978110953
SN - 0022-202X
VL - 136
SP - 809
EP - 818
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 4
ER -