Silencing of the Gene by Aberrant Promoter Methylation is Associated with a Poor Patient Outcome and Promotes Cell Proliferation and Migration in Clear Cell Renal Cell Carcinoma

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2021 Apr 5

PMID 33816562

Citations 5

Authors

Ying Gan

Congcong Cao

Aolin Li

Haifeng Song

Guanyu Kuang

Binglei Ma

Quan Zhang

Qian Zhang

Affiliations

Soon will be listed here.

Abstract

To investigate the underlying molecular mechanism of tripartite motif-containing 58 (TRIM58) in the development of clear cell renal cell carcinoma (ccRCC), we explored TRIM58 expression and methylation in tumor tissues and the association with clinicopathological features and prognosis of tissue samples; Moreover, we examined the direct gene transcription of TRIM58-specific DNA demethyltransferase (TRIM58-TET1) by the CRISPR-dCas9 fused with the catalytic domain of TET1 and the biological functions in RCC cells. In this study, we demonstrate that TRIM58 is frequently downregulated by promoter methylation in ccRCC tissues, associated significantly with tumor nuclear grade and poor patient survival. TRIM58-TET1 directly induces demethylation of TRIM58 CpG islands, and activates TRIM58 transcription in RCC cell lines. Besides, DNA demethylation of TRIM58 by TRIM58-TET1 significantly inhibits cell proliferation and migration Overall, our results demonstrate that TRIM58 is inactivated by promoter methylation, associates with tumor nuclear grade and poor survival, and TRIM58 DNA demethylation could directly activate TRIM58 transcription and inhibit cell proliferation and migration in RCC cell lines.

Citing Articles

Multifaceted role of in health and disease.

Maghsoudloo M, Mokhtari K, Jamali B, Gholamzad A, Entezari M, Hashemi M MedComm (2020). 2024; 5(11):e790.

PMID: 39534556 PMC: 11554878. DOI: 10.1002/mco2.790.

Profiling genetically driven alternative splicing across the Indonesian archipelago.

Ibeh N, Kusuma P, Crenna Darusallam C, Malik S, Sudoyo H, McCarthy D Am J Hum Genet. 2024; 111(11):2458-2477.

PMID: 39383868 PMC: 11568790. DOI: 10.1016/j.ajhg.2024.09.004.

Targeted DNA Demethylation: Vectors, Effectors and Perspectives.

Yano N, Fedulov A Biomedicines. 2023; 11(5).

PMID: 37239005 PMC: 10215725. DOI: 10.3390/biomedicines11051334.

Predictive and Prognostic Value of TRIM58 Protein Expression in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.

Zheng Y, Li J, Ning L, Xie N Breast Cancer (Dove Med Press). 2022; 14:475-487.

PMID: 36578908 PMC: 9790805. DOI: 10.2147/BCTT.S387209.

Pan-cancer illumination of TRIM gene family reveals immunology regulation and potential therapeutic implications.

Gao Y, Pan T, Xu G, Li S, Guo J, Zhang Y Hum Genomics. 2022; 16(1):65.

PMID: 36461099 PMC: 9719184. DOI: 10.1186/s40246-022-00441-9.

References

Wang L, Fan Y, Zhang L, Li L, Kuang G, Luo C . Classic SRY-box protein SOX7 functions as a tumor suppressor regulating WNT signaling and is methylated in renal cell carcinoma. FASEB J. 2018; 33(1):254-263. DOI: 10.1096/fj.201701453RR. View

Zhang W, Cui Q, Qu W, Ding X, Jiang D, Liu H . TRIM58/cg26157385 methylation is associated with eight prognostic genes in lung squamous cell carcinoma. Oncol Rep. 2018; 40(1):206-216. PMC: 6059744. DOI: 10.3892/or.2018.6426. View

Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K . Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. Nat Biotechnol. 2016; 34(10):1060-1065. DOI: 10.1038/nbt.3658. View

Sharma S, Kelly T, Jones P . Epigenetics in cancer. Carcinogenesis. 2009; 31(1):27-36. PMC: 2802667. DOI: 10.1093/carcin/bgp220. View

Moch H . An overview of renal cell cancer: pathology and genetics. Semin Cancer Biol. 2012; 23(1):3-9. DOI: 10.1016/j.semcancer.2012.06.006. View

Kardooni H, Gonzalez-Gualda E, Stylianakis E, Saffaran S, Waxman J, Kypta R . CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer. Cancers (Basel). 2018; 10(6). PMC: 6025141. DOI: 10.3390/cancers10060165. View

Joosten S, Smits K, Aarts M, Melotte V, Koch A, Tjan-Heijnen V . Epigenetics in renal cell cancer: mechanisms and clinical applications. Nat Rev Urol. 2018; 15(7):430-451. DOI: 10.1038/s41585-018-0023-z. View

Christoph F, Weikert S, Kempkensteffen C, Krause H, Schostak M, Kollermann J . Promoter hypermethylation profile of kidney cancer with new proapoptotic p53 target genes and clinical implications. Clin Cancer Res. 2006; 12(17):5040-6. DOI: 10.1158/1078-0432.CCR-06-0144. View

Hirata H, Hinoda Y, Nakajima K, Kawamoto K, Kikuno N, Ueno K . Wnt antagonist DKK1 acts as a tumor suppressor gene that induces apoptosis and inhibits proliferation in human renal cell carcinoma. Int J Cancer. 2010; 128(8):1793-803. DOI: 10.1002/ijc.25507. View

10.

Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S, Astuti D . Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma. Cancer Res. 2001; 61(19):7277-81. View

11.

Chavez A, Scheiman J, Vora S, Pruitt B, Tuttle M, Iyer E . Highly efficient Cas9-mediated transcriptional programming. Nat Methods. 2015; 12(4):326-8. PMC: 4393883. DOI: 10.1038/nmeth.3312. View

12.

Xu R, Xu Q, Huang G, Yin X, Zhu J, Peng Y . Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma. Biomed Res Int. 2020; 2019:9379864. PMC: 6949667. DOI: 10.1155/2019/9379864. View

13.

Ricketts C, Hill V, Linehan W . Tumor-specific hypermethylation of epigenetic biomarkers, including SFRP1, predicts for poorer survival in patients from the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) project. PLoS One. 2014; 9(1):e85621. PMC: 3893219. DOI: 10.1371/journal.pone.0085621. View

14.

Liu X, Long Z, Cai H, Yu S, Wu J . TRIM58 suppresses the tumor growth in gastric cancer by inactivation of β-catenin signaling via ubiquitination. Cancer Biol Ther. 2019; 21(3):203-212. PMC: 7012179. DOI: 10.1080/15384047.2019.1679554. View

15.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

16.

Malouf G, Su X, Zhang J, Creighton C, Ho T, Lu Y . DNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas. Clin Cancer Res. 2016; 22(24):6236-6246. PMC: 5135666. DOI: 10.1158/1078-0432.CCR-15-1217. View

17.

Zhang Q, Zhang L, Li L, Wang Z, Ying J, Fan Y . Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis. Cancer Lett. 2014; 354(2):227-34. DOI: 10.1016/j.canlet.2014.07.040. View

18.

Bikard D, Jiang W, Samai P, Hochschild A, Zhang F, Marraffini L . Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Nucleic Acids Res. 2013; 41(15):7429-37. PMC: 3753641. DOI: 10.1093/nar/gkt520. View

19.

Kajiura K, Masuda K, Naruto T, Kohmoto T, Watabnabe M, Tsuboi M . Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma. Oncotarget. 2016; 8(2):2890-2905. PMC: 5356850. DOI: 10.18632/oncotarget.13761. View

20.

Alt A, Boorjian S, Lohse C, Costello B, Leibovich B, Blute M . Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011; 117(13):2873-82. DOI: 10.1002/cncr.25836. View