Expression of SAMHD1 and its mutation on prognosis of colon cancer

Zhang,Zhou; Li,Ping; Sun,Ping

doi:10.3892/ol.2022.13423

Expression of SAMHD1 and its mutation on prognosis of colon cancer

Authors:
- Zhou Zhang
- Ping Li
- Ping Sun
View Affiliations

Affiliations: Translational Medical Centre, Wuxi No. 2 People's Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, Jiangsu 214002, P.R. China, Department of Pathology, Wuxi No. 2 People's Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, Jiangsu 214002, P.R. China
Published online on: July 8, 2022 https://doi.org/10.3892/ol.2022.13423
Article Number: 303
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The expression of sterile α motif and histidine/aspartic acid domain‑containing protein 1 (SAMHD1) and its mutation play a key role in the prognosis of colon cancer. The aim of the present study was to investigate the mechanism and the role of SAMHD1 in colon cancer. Microarray data from 187 patients with colon cancer and 45 adjacent normal tissue obtained from the Gene Expression Omnibus (GEO) were analyzed. A protein‑protein interaction (PPI) network was constructed to identify key genes associated with colon cancer prognosis. Cox proportional hazard regression and survival analyses were performed to identify the potential for SAMHD1 to serve as a prognostic biomarker. Immunohistochemistry (IHC) and immunofluorescence (IF) were performed to assess the expression levels and distribution of SAMHD1 in tissues and cells. Western blotting (WB) and Cell Counting Kit‑8 (CCK‑8) assays were used to identify the proliferation and apoptotic effects of SAMHD1 on HT‑29 (Cas9‑SAMHD1) cell lines. A total of 6,905 consistently differentially expressed genes were identified in the GEO database. Through the PPI network, SAMHD1 was found to be associated with Kirsten rat sarcoma virus (KRAS). SAMHD1 expression was negatively associated with KRAS. Proportional hazards regression and survival analyses demonstrated that low expression of SAMHD1 was associated with increased patient mortality. IHC and IF results demonstrated that SAMHD1 expression in patients with colon cancer was decreased compared with controls (both P<0.05). CCK‑8 and WB results showed that proliferation was significantly promoted, and the expression levels of apoptosis‑related proteins were significantly inhibited in the D137N and D311A groups as a result of a mutation in the deoxynucleoside triphosphohydrolase (dNTPase) site (both P<0.05 vs. wild‑type). Proliferation was inhibited and apoptosis‑related protein expression levels were promoted in the wild‑type (WT) and D137N groups following 20 µg/ml 5‑fluorouracil (5‑FU) treatment (both P<0.05). WB and CCK‑8 results showed cell proliferation was promoted and cell apoptosis‑related protein expression was inhibited in the D137N group following treatment with 20 µg/ml 5‑FU (all P<0.05) compared with the WT group. In conclusion, SAMHD1 expression was low in colon cancer. The dNTPase function of SAMHD1 may inhibit colon cancer cell proliferation and may enhance apoptosis. In addition, first‑line chemotherapy with 5‑FU has a time‑dependent effect, which may provide novel options for clinical treatment of colon cancer.

View Figures

View References

1	Marley AR and Nan H: Epidemiology of colorectal cancer. Int J Mol Epidemiol Genet. 7:105–114. 2016.
2	Labianca R, Beretta GD, Kildani B, Milesi L, Merlin F, Mosconi S, Pessi MA, Prochilo T, Quadri A, Gatta G, et al: Colon cancer. Crit Rev Oncol Hematol. 74:106–133. 2010. View Article : Google Scholar
3	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
4	Chiang CJ, Lo WC, Yang YW, You SL, Chen CJ and Lai MS: Incidence and survival of adult cancer patients in Taiwan, 2002–2012. J Formos Med Assoc. 115:1076–1088. 2016. View Article : Google Scholar
5	Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A and Jemal A: Colorectal cancer statistics, 2017. CA Cancer J Clin. 67:177–193. 2017. View Article : Google Scholar : PubMed/NCBI
6	Lemmens V, van Steenbergen L, Janssen-Heijnen M, Martijn H, Rutten H and Coebergh JW: Trends in colorectal cancer in the south of the Netherlands 1975–2007: Rectal cancer survival levels with colon cancer survival. Acta Oncol. 49:784–796. 2010. View Article : Google Scholar
7	Wu C: Systemic therapy for colon cancer. Surg Oncol Clin N Am. 27:235–242. 2018. View Article : Google Scholar : PubMed/NCBI
8	Zhang Z, Zheng L, Yu Y, Wu J, Yang F, Xu Y, Guo Q, Wu X, Cao S, Cao L and Song X: Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (review). Int J Oncol. 56:879–888. 2020.
9	Tang C, Ji X, Wu L and Xiong Y: Impaired dNTPase activity of SAMHD1 by phosphomimetic mutation of Thr-592. J Biol Chem. 290:26352–26359. 2015. View Article : Google Scholar : PubMed/NCBI
10	Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI, Christodoulou E, Walker PA, Kelly G, Haire LF, Yap MW, et al: HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature. 480:379–382. 2011. View Article : Google Scholar : PubMed/NCBI
11	Sommer AF, Rivière L, Qu B, Schott K, Riess M, Ni Y, Shepard C, Schnellbächer E, Finkernagel M, Himmelsbach K, et al: Restrictive influence of SAMHD1 on hepatitis B virus life cycle. Sci Rep. 6:266162016. View Article : Google Scholar : PubMed/NCBI
12	Ryoo J, Choi J, Oh C, Kim S, Seo M, Kim SY, Seo D, Kim J, White TE, Brandariz-Nuñez A, et al: The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med. 20:936–941. 2014. View Article : Google Scholar : PubMed/NCBI
13	Antonucci JM, St Gelais C, de Silva S, Yount JS, Tang C, Ji X, Shepard C, Xiong Y, Kim B and Wu L: SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. Nat Med. 22:1072–1074. 2016. View Article : Google Scholar : PubMed/NCBI
14	Leshinsky-Silver E, Malinger G, Ben-Sira L, Kidron D, Cohen S, Inbar S, Bezaleli T, Levine A, Vinkler C, Lev D and Lerman-Sagie T: A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Goutiéres syndrome associated with mtDNA deletions. Eur J Hum Genet. 19:287–292. 2011. View Article : Google Scholar
15	Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, et al: Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 41:829–832. 2009. View Article : Google Scholar
16	Thiele H, du Moulin M, Barczyk K, George C, Schwindt W, Nürnberg G, Frosch M, Kurlemann G, Roth J, Nürnberg P and Rutsch F: Cerebral arterial stenoses and stroke: Novel features of Aicardi-Goutières syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression. Hum Mutat. 31:E1836–E1850. 2010. View Article : Google Scholar
17	Dale RC, Gornall H, Singh-Grewal D, Alcausin M, Rice GI and Crow YJ: Familial Aicardi-Goutières syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures. Am J Med Genet A. 152A:938–942. 2010. View Article : Google Scholar : PubMed/NCBI
18	de Silva S, Hoy H, Hake TS, Wong HK, Porcu P and Wu L: Promoter methylation regulates SAMHD1 gene expression in human CD4+ T cells. J Biol Chem. 288:9284–9292. 2013. View Article : Google Scholar : PubMed/NCBI
19	de Silva S, Wang F, Hake TS, Porcu P, Wong HK and Wu L: Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sézary syndrome patients. J Invest Dermatol. 134:562–565. 2014. View Article : Google Scholar
20	Wang JL, Lu FZ, Shen XY, Wu Y and Zhao LT: SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation. Biochem Biophys Res Commun. 455:229–233. 2014. View Article : Google Scholar : PubMed/NCBI
21	Lee EJ, Seo JH, Park JH, Vo TTL, An S, Bae SJ, Le H, Lee HS, Wee HJ, Lee D, et al: SAMHD1 acetylation enhances its deoxynucleotide triphosphohydrolase activity and promotes cancer cell proliferation. Oncotarget. 8:68517–68529. 2017. View Article : Google Scholar
22	Cribier A, Descours B, Valadao AL, Laguette N and Benkirane M: Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Rep. 3:1036–1043. 2013. View Article : Google Scholar : PubMed/NCBI
23	Rentoft M, Lindell K, Tran P, Chabes AL, Buckland RJ, Watt DL, Marjavaara L, Nilsson AK, Melin B, Trygg J, et al: Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance. Proc Natl Acad Sci USA. 113:4723–4728. 2016. View Article : Google Scholar : PubMed/NCBI
24	Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, Cole CG, Ward S, Dawson E, Ponting L, et al: COSMIC: Somatic cancer genetics at high-resolution. Nucleic Acids Res. 45(D1): D777–D783. 2017. View Article : Google Scholar : PubMed/NCBI
25	Doncheva NT, Morris JH, Gorodkin J and Jensen LJ: Cytoscape StringApp: Network analysis and visualization of proteomics data. J Proteome Res. 18:623–632. 2019. View Article : Google Scholar : PubMed/NCBI
26	Felip E, Gutiérrez-Chamorro L, Gómez M, Garcia-Vidal E, Romeo M, Morán T, Layos L, Pérez-Roca L, Riveira-Muñoz E, Clotet B, et al: Modulation of DNA damage response by SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase (SAMHD1) determines prognosis and treatment efficacy in different solid tumor types. Cancers (Basel). 14:6412022. View Article : Google Scholar : PubMed/NCBI
27	Janardhan KS, Jensen H, Clayton NP and Herbert RA: Immunohistochemistry in investigative and toxicologic pathology. Toxicol Pathol. 46:488–510. 2018. View Article : Google Scholar
28	Xu C, Zhang W, Liu S, Wu W, Qin M and Huang J: Activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer cells. Oncol Lett. 15:9719–9724. 2018.
29	Yu X, Du Z, Sun X, Shi C, Zhang H and Hu T: Aberrant Cosmc genes result in Tn antigen expression in human colorectal carcinoma cell line HT-29. Int J Clin Exp Pathol. 8:2590–2602. 2015.
30	Kim SJ, Kim HJ, Kim HR, Lee SH, Cho SD, Choi CS, Nam JS and Jung JY: Antitumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Mol Med Rep. 6:1443–1449. 2012. View Article : Google Scholar : PubMed/NCBI
31	Li Q, Zhou X, Fang Z and Zhou H: Knockdown of KLK12 inhibits viability and induces apoptosis in human colorectal cancer HT-29 cell line. Int J Mol Med. 44:1667–1676. 2019.PubMed/NCBI
32	Guo H, Wu L, Zhao P and Feng A: Overexpression of long non-coding RNA zinc finger antisense 1 in acute myeloid leukemia cell lines influences cell growth and apoptosis. Exp Ther Med. 14:647–651. 2017. View Article : Google Scholar : PubMed/NCBI
33	Siddiqui AD and Piperdi B: KRAS mutation in colon cancer: A marker of resistance to EGFR-I therapy. Ann Surg Oncol. 17:1168–1176. 2010. View Article : Google Scholar
34	Li N, Zhang W and Cao X: Identification of human homologue of mouse IFN-gamma induced protein from human dendritic cells. Immunol Lett. 74:221–224. 2000. View Article : Google Scholar
35	Kueck T, Cassella E, Holler J, Kim B and Bieniasz PD: The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression. Elife. 7:e388672018. View Article : Google Scholar : PubMed/NCBI
36	Kodigepalli KM, Li M, Liu SL and Wu L: Exogenous expression of SAMHD1 inhibits proliferation and induces apoptosis in cutaneous T-cell lymphoma-derived HuT78 cells. Cell Cycle. 16:179–188. 2017. View Article : Google Scholar : PubMed/NCBI
37	Schneider C, Oellerich T, Baldauf HM, Schwarz SM, Thomas D, Flick R, Bohnenberger H, Kaderali L, Stegmann L, Cremer A, et al: SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nat Med. 23:250–255. 2017. View Article : Google Scholar : PubMed/NCBI
38	Clifford R, Louis T, Robbe P, Ackroyd S, Burns A, Timbs AT, Wright Colopy G, Dreau H, Sigaux F, Judde JG, et al: SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood. 123:1021–1031. 2014. View Article : Google Scholar : PubMed/NCBI
39	Rossi D: SAMHD1: A new gene for CLL. Blood. 123:951–952. 2014. View Article : Google Scholar : PubMed/NCBI
40	Herold N, Rudd SG, Sanjiv K, Kutzner J, Bladh J, Paulin CBJ, Helleday T, Henter JI and Schaller T: SAMHD1 protects cancer cells from various nucleoside-based antimetabolites. Cell Cycle. 16:1029–1038. 2017. View Article : Google Scholar : PubMed/NCBI
41	Rudd SG, Schaller T and Herold N: SAMHD1 is a barrier to antimetabolite-based cancer therapies. Mol Cell Oncol. 4:e12875542017. View Article : Google Scholar
42	Zhu KW, Chen P, Zhang DY, Yan H, Liu H, Cen LN, Liu YL, Cao S, Zhou G, Zeng H, et al: Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML). J Transl Med. 16:902018. View Article : Google Scholar : PubMed/NCBI
43	Kohnken R, Kodigepalli KM and Wu L: Regulation of deoxynucleotide metabolism in cancer: Novel mechanisms and therapeutic implications. Mol Cancer. 14:1762015. View Article : Google Scholar : PubMed/NCBI
44	Mauney CH and Hollis T: SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity. Autoimmunity. 51:96–110. 2018. View Article : Google Scholar : PubMed/NCBI
45	Wang Z, Bhattacharya A, Villacorta J, Diaz-Griffero F and Ivanov DN: Allosteric activation of SAMHD1 protein by deoxynucleotide triphosphate (dNTP)-dependent tetramerization requires dNTP concentrations that are similar to dNTP concentrations observed in cycling T cells. J Biol Chem. 291:21407–21413. 2016. View Article : Google Scholar : PubMed/NCBI
46	Bonifati S, Daly MB, St Gelais C, Kim SH, Hollenbaugh JA, Shepard C, Kennedy EM, Kim DH, Schinazi RF, Kim B and Wu L: SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells. Virology. 495:92–100. 2016. View Article : Google Scholar : PubMed/NCBI
47	Herrmann A, Wittmann S, Thomas D, Shepard CN, Kim B, Ferreirós N and Gramberg T: The SAMHD1-mediated block of LINE-1 retroelements is regulated by phosphorylation. Mob DNA. 9:112018. View Article : Google Scholar : PubMed/NCBI
48	Yang CA, Huang HY, Chang YS, Lin CL, Lai IL and Chang JG: DNA-sensing and nuclease gene expressions as markers for colorectal cancer progression. Oncology. 92:115–124. 2017. View Article : Google Scholar : PubMed/NCBI
49	Jiang H, Li C and Liu Z: Shengjing Hospital and Hu: Expression and relationship of SAMHD1 with other apoptotic and autophagic genes in acute myeloid leukemia patients. Acta Haematol. 143:51–59. 2020. View Article : Google Scholar