SIRT6 is upregulated and associated with cancer aggressiveness in papillary thyroid cancer via BRAF/ERK/Mcl‑1 pathway

Qu,Ning; Hu,Jia‑Qian; Liu,Liang; Zhang,Ting‑Ting; Sun,Guo‑Hua; Shi,Rong‑Liang; Ji,Qing‑Hai

doi:10.3892/ijo.2017.3951

SIRT6 is upregulated and associated with cancer aggressiveness in papillary thyroid cancer via BRAF/ERK/Mcl‑1 pathway

Authors:
- Ning Qu
- Jia‑Qian Hu
- Liang Liu
- Ting‑Ting Zhang
- Guo‑Hua Sun
- Rong‑Liang Shi
- Qing‑Hai Ji
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Affiliations: Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China, Department of Radiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
Published online on: April 5, 2017 https://doi.org/10.3892/ijo.2017.3951
Pages: 1683-1692

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Abstract

Sirtuin 6 (SIRT6) is a member of the SIRT family NAD+‑dependent deacetylases reported to function in controlling organism homeostasis, lifespan, and diseases. This study investigated the role of SIRT6 in papillary thyroid cancer (PTC). Data of 391 PTC patients was extracted from The Cancer Genome Atlas database to investigate the expression of SIRTs (SIRT1‑7) and their relationship with clinicopathological parameters. Additional 45 pairs of PTC tumor tissues and corresponding non‑tumor tissues were studied using microarray analysis for SIRT6 expression. Surgically resected, pathologically diagnosed tissues from 130 in‑house PTC patients were used for confirmation of SIRT6 expression. SIRT6 silenced K1 and TPC‑1 cells were generated to explore the influence of SIRT6 on cancer cell aggressiveness in vitro. SIRT6 mRNA and protein levels were upregulated in PTC tumor tissues and its overexpression was an independent biomarker for nodal metastasis (odds ratio=1.794, 95% confidence interval: 1.256‑1.920, p=0.012). SIRT6 expression was related to poor recurrence‑free survival, however, not significantly. Silencing SIRT6 downregulated PTC cell aggressiveness in vitro by suppressing ERK and Mcl‑1. In conclusion, these results suggest that SIRT6 enhances cell aggressiveness in PTC via BRAF/ERK/Mcl‑1 pathway, and thus may be a promising target in the treatment of the disease.

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1	Davies L and Welch HG: Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg. 140:317–322. 2014. View Article : Google Scholar : PubMed/NCBI
2	Colonna M, Uhry Z, Guizard AV, Delafosse P, Schvartz C, Belot A and Grosclaude P; FRANCIM network: Recent trends in incidence, geographical distribution, and survival of papillary thyroid cancer in France. Cancer Epidemiol. 39:511–518. 2015. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
4	McLeod DS, Sawka AM and Cooper DS: Controversies in primary treatment of low-risk papillary thyroid cancer. Lancet. 381:1046–1057. 2013. View Article : Google Scholar : PubMed/NCBI
5	La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F and Negri E: Thyroid cancer mortality and incidence: A global overview. Int J Cancer. 136:2187–2195. 2015. View Article : Google Scholar
6	Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlová B, Yip L, Mian C, et al: Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 33:42–50. 2015. View Article : Google Scholar :
7	Grogan RH, Kaplan SP, Cao H, Weiss RE, Degroot LJ, Simon CA, Embia OM, Angelos P, Kaplan EL and Schechter RB: A study of recurrence and death from papillary thyroid cancer with 27 years of median follow-up. Surgery. 154:1436–1446; discussion 1446–1447. 2013. View Article : Google Scholar : PubMed/NCBI
8	Bartosch C, Monteiro-Reis S, Almeida-Rios D, Vieira R, Castro A, Moutinho M, Rodrigues M, Graça I, Lopes JM and Jerónimo C: Assessing sirtuin expression in endometrial carcinoma and non-neoplastic endometrium. Oncotarget. 7:1144–1154. 2016.
9	Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, Mottis A, Jo YS, Viswanathan M, Schoonjans K, et al: The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell. 154:430–441. 2013. View Article : Google Scholar : PubMed/NCBI
10	Lai CC, Lin PM, Lin SF, Hsu CH, Lin HC, Hu ML, Hsu CM and Yang MY: Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumour Biol. 34:1847–1854. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zhang X, Khan S, Jiang H, Antonyak MA, Chen X, Spiegelman NA, Shrimp JH, Cerione RA and Lin H: Identifying the functional contribution of the defatty-acylase activity of SIRT6. Nat Chem Biol. 12:614–620. 2016. View Article : Google Scholar : PubMed/NCBI
12	Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa S, et al: SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell. 51:454–468. 2013. View Article : Google Scholar : PubMed/NCBI
13	Wang WW, Zeng Y, Wu B, Deiters A and Liu WR: A chemical biology approach to reveal Sirt6-targeted Histone H3 sites in nucleosomes. ACS Chem Biol. 11:1973–1981. 2016. View Article : Google Scholar : PubMed/NCBI
14	Kugel S, Sebastián C, Fitamant J, Ross KN, Saha SK, Jain E, Gladden A, Arora KS, Kato Y, Rivera MN, et al: SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell. 165:1401–1415. 2016. View Article : Google Scholar : PubMed/NCBI
15	Marquardt JU, Fischer K, Baus K, Kashyap A, Ma S, Krupp M, Linke M, Teufel A, Zechner U, Strand D, et al: Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients. Hepatology. 58:1054–1064. 2013. View Article : Google Scholar : PubMed/NCBI
16	Elhanati S, Ben-Hamo R, Kanfi Y, Varvak A, Glazz R, Lerrer B, Efroni S and Cohen HY: Reciprocal regulation between SIRT6 and miR-122 controls liver metabolism and predicts hepatocarcinoma prognosis. Cell Rep. 14:234–242. 2016. View Article : Google Scholar : PubMed/NCBI
17	Thirumurthi U, Shen J, Xia W, LaBaff AM, Wei Y, Li CW, Chang WC, Chen CH, Lin HK, Yu D, et al: MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer. Sci Signal. 7:ra712014. View Article : Google Scholar : PubMed/NCBI
18	Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yagüe E, Cavaco TB, Khongkow P, Man EP, Laohasinnarong S, et al: SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis. 34:1476–1486. 2013. View Article : Google Scholar : PubMed/NCBI
19	Ming M, Han W, Zhao B, Sundaresan NR, Deng CX, Gupta MP and He YY: SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer Res. 74:5925–5933. 2014. View Article : Google Scholar : PubMed/NCBI
20	Xie Q, Wong AS and Xia W: SIRT6 induces EMT and promotes cancer cell invasion and migration in prostate cancer. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research. Cancer Res. 74(Suppl 19): Abst 1151. 2014. View Article : Google Scholar
21	Kugel S, Feldman JL, Klein MA, Silberman DM, Sebastián C, Mermel C, Dobersch S, Clark AR, Getz G, Denu JM, et al: Identification of and molecular basis for SIRT6 loss-of-lunction point mutations in cancer. Cell Rep. 13:479–488. 2015. View Article : Google Scholar : PubMed/NCBI
22	Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, Ram O, Truelove J, Guimaraes AR, Toiber D, et al: The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 151:1185–1199. 2012. View Article : Google Scholar : PubMed/NCBI
23	Bai L, Lin G, Sun L, Liu Y, Huang X, Cao C, Guo Y and Xie C: Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway. Oncotarget. 7:40377–40386. 2016.PubMed/NCBI
24	Liu X, Qu S, Liu R, Sheng C, Shi X, Zhu G, Murugan AK, Guan H, Yu H, Wang Y, et al: TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab. 99:E1130–E1136. 2014. View Article : Google Scholar : PubMed/NCBI
25	Howell GM, Nikiforova MN, Carty SE, Armstrong MJ, Hodak SP, Stang MT, McCoy KL, Nikiforov YE and Yip L: BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer. Ann Surg Oncol. 20:47–52. 2013. View Article : Google Scholar
26	Becker TM, Boyd SC, Mijatov B, Gowrishankar K, Snoyman S, Pupo GM, Scolyer RA, Mann GJ, Kefford RF, Zhang XD, et al: Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene. 33:1158–1166. 2014. View Article : Google Scholar
27	Kawakami H, Huang S, Pal K, Dutta SK, Mukhopadhyay D and Sinicrope FA: Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer. Mol Cancer Ther. 15:3015–3027. 2016. View Article : Google Scholar : PubMed/NCBI
28	Liu D, Liu J, Lin B, Liu S, Hou R, Hao Y, Liu Q, Zhang S and Iwamori M: Lewis y regulate cell cycle related factors in ovarian carcinoma cell RMG-I in vitro via ERK and Akt signaling pathways. Int J Mol Sci. 13:828–839. 2012. View Article : Google Scholar : PubMed/NCBI
29	He K, Chen D, Ruan H, Li X, Tong J, Xu X, Zhang L and Yu J: BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells. Oncotarget. 7:47699–47710. 2016.PubMed/NCBI
30	Gao M, Kong Q, Hua H, Yin Y, Wang J, Luo T and Jiang Y: AMPK-mediated up-regulation of mTORC2 and MCL-1 compromises the anti-cancer effects of aspirin. Oncotarget. 7:16349–16361. 2016.PubMed/NCBI
31	Feng XX, Luo J, Liu M, Yan W, Zhou ZZ, Xia YJ, Tu W, Li PY, Feng ZH and Tian DA: Sirtuin 6 promotes transforming growth factor-β1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence. Cancer Sci. 106:559–566. 2015. View Article : Google Scholar : PubMed/NCBI
32	Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, et al: SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell. 136:62–74. 2009. View Article : Google Scholar : PubMed/NCBI
33	Cheng MY, Cheng YW, Yan J, Hu XQ, Zhang H, Wang ZR, Yin Q and Cheng W: SIRT6 suppresses mitochondrial defects and cell death via the NF-κB pathway in myocardial hypoxia/reoxygenation induced injury. Am J Transl Res. 8:5005–5015. 2016.