Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics

Abstract

SI RT6 is an important histone modifying protein that regulates DNA repair, telomere maintenance, energy metabolism, and target gene expression. Recently SIRT6 has been identifi ed as a tumor suppressor and is downregulated in certain cancer types, but not in other cancers. From deposited gene profi ling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal or paratumor prostate tissues. Tissue microarray studies confi rmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cycle, increased apoptosis, elevated DNA damage level and decrease in BCL2 gene expression. Moreover, SIRT6-deficiency reduced cell viability and enhanced chemotherapeutics sensitivity. Taken together, this study provides the fi rst evidence of SIRT6 overexpression in human prostate cancer, and SIRT6 regulation could be exploited for prostate cancer therapy.

Keywords

SI RT6 / overexpression / prostate cancer / therapy

References

[1] Bauer, I., Grozio, A., Lasiglie, D., Basile, G., Sturla, L., Magnone, M., Sociali, G., Soncini, D., Caffa, I., Poggi, A., . (2012). The NAD+- dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem 287, 40924-40937 .10.1074/jbc.M112.405837
[2] Bosch-Presegue, L., and Vaquero, A. (2011). The dual role of sirtuins in cancer. Genes Cancer 2, 648-662 .10.1177/1947601911417862
[3] Cardus, A., Uryga, A.K., Walters, G., and Erusalimsky, J.D. (2013). SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence. Cardiovasc Res 97, 571-579 .10.1093/cvr/cvs352
[4] Haigis, M.C., and Sinclair, D.A. (2010). Mammalian sirtuins: biological insights and disease relevance. Ann Rev Pathol 5, 253-295 .10.1146/annurev.pathol.4.110807.092250
[5] Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646-674 .10.1016/j.cell.2011.02.013
[6] Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D. (2011). Global cancer statistics. CA: a cancer journal for clinicians 61, 69-90 .10.3322/caac.20107
[7] Kaidi, A., Weinert, B.T., Choudhary, C., and Jackson, S.P. (2010). Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329, 1348-1353 .10.1126/science.1192049
[8] Kawahara, T.L., Michishita, E., Adler, A.S., Damian, M., Berber, E., Lin, M., McCord, R.A., Ongaigui, K.C., Boxer, L.D., Chang, H.Y., . (2009). SIRT6 links histone H3 lysine 9 deacetylation to NFkappaBdependent gene expression and organismal life span. Cell 136, 62-74 .10.1016/j.cell.2008.10.052
[9] Kawahara, T.L., Rapicavoli, N.A., Wu, A.R., Qu, K., Quake, S.R., and Chang, H.Y. (2011). Dynamic chromatin localization of Sirt6 shapes stress- and aging-related transcriptional networks. PLoS Genet 7, e1002153.10.1371/journal.pgen.1002153
[10] Khongkow, M., Olmos, Y., Gong, C., Gomes, A.R., Monteiro, L.J., Yague, E., Cavaco, T.B., Khongkow, P., Man, E.P., Laohasinnarong, S., . (2013). SIRT6 modulates pa epirubicin resistance and survival in breast cancer. Carcinogenesis .34, 1476-1486 .10.1093/carcin/bgt098
[11] Liszt, G., Ford, E., Kurtev, M., and Guarente, L. (2005). Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 280, 21313-21320 .10.1074/jbc.M413296200
[12] Marquardt, J.U., Fischer, K., Baus, K., Kashyap, A., Ma, S., Krupp, M., Linke, M., Teufel, A., Zechner, U., Strand, D., . (2013). SIRT6 dependent genetic and epigenetic alterations are associated with poor clinical outcome in HCC patients. Hepatology .(In Press).10.1002/hep.26413
[13] McCord, R.A., Michishita, E., Hong, T., Berber, E., Boxer, L.D., Kusumoto, R., Guan, S., Shi, X., Gozani, O., Burlingame, A.L., . (2009). SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging 1, 109-121 .
[14] Michishita, E., Park, J.Y., Burneskis, J.M., Barrett, J.C., and Horikawa, I. (2005). Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16, 4623-4635 .10.1091/mbc.E05-01-0033
[15] Min, L., Ji, Y., Bakiri, L., Qiu, Z., Cen, J., Chen, X., Chen, L., Scheuch, H., Zheng, H., Qin, L., . (2012). Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat Cell Biol 14, 1203-1211 .10.1038/ncb2590
[16] Mostoslavsky, R., Chua, K.F., Lombard, D.B., Pang, W.W., Fischer, M.R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M.M., . (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315-329 .10.1016/j.cell.2005.11.044
[17] Sebastian, C., Zwaans, B.M., Silberman, D.M., Gymrek, M., Goren, A., Zhong, L., Ram, O., Truelove, J., Guimaraes, A.R., Toiber, D., . (2012). The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185-1199 .10.1016/j.cell.2012.10.047
[18] Shah, R.B., Mehra, R., Chinnaiyan, A.M., Shen, R., Ghosh, D., Zhou, M., Macvicar, G.R., Varambally, S., Harwood, J., Bismar, T.A., . (2004). Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 64, 9209-9216 .10.1158/0008-5472.CAN-04-2442
[19] Song, N.Y., and Surh, Y.J. (2012). Janus-faced role of SIRT1 in tumorigenesis. Ann N Y Acad Sci 1271, 10-19 .10.1111/j.1749-6632.2012.06762.x
[20] Sundaresan, N.R., Vasudevan, P., Zhong, L., Kim, G., Samant, S., Parekh, V., Pillai, V.B., Ravindra, P.V., Gupta, M., Jeevanandam, V., . (2012). The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med 18, 1643-1650 .10.1038/nm.2961
[21] Taylor, B.S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B.S., Arora, V.K., Kaushik, P., Cerami, E., Reva, B., . (2010). Integrative genomic profi ling of human prostate cancer. Cancer Cell 18, 11-22 .10.1016/j.ccr.2010.05.026
[22] Van Meter, M., Mao, Z., Gorbunova, V., and Seluanov, A. (2011). SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell Cycle 10, 3153-3158 .10.4161/cc.10.18.17435
[23] Xiao, C., Wang, R.H., Lahusen, T.J., Park, O., Bertola, A., Maruyama, T., Reynolds, D., Chen, Q., Xu, X., Young, H.A., . (2012). Progression of chronic liver infl ammation and fi brosis driven by activation of cJUN signaling in Sirt6 mutant mice. J Biol Chem 287, 41903-41913 .10.1074/jbc.M112.415182
[24] Xie, Q.R., Liu, Y., Shao, J., Yang, J., Liu, T., Zhang, T., Wang, B., Mruk, D.D., Silvestrini, B., Cheng, C.Y., . (2013). Male contraceptive Adjudin is a potential anti-cancer drug. Biochem Pharmacol 85, 345-355 .10.1016/j.bcp.2012.11.008
[25] Xie, X., Zhang, H., Gao, P., Wang, L., Zhang, A., Xie, S., and Li, J. (2012). Overexpression of SIRT6 in porcine fetal fi broblasts attenuates cytotoxicity and premature senescence caused by D-galactose and tert-butylhydroperoxide. DNA Cell Biol 31, 745-752 .10.1089/dna.2011.1435
[26] Zhong, L., D’Urso, A., Toiber, D., Sebastian, C., Henry, R.E., Vadysirisack, D.D., Guimaraes, A., Marinelli, B., Wikstrom, J.D., Nir, T., . (2010). The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140, 280-293 .10.1016/j.cell.2009.12.041