Sohlh2 Inhibits the Malignant Progression of Renal Cell Carcinoma by Upregulating Klotho DNMT3a

Overview

Journal Front Oncol

Specialty Oncology

Date 2022 Feb 7

PMID 35127476

Authors

Yang Liu

Weiwei Cui

Ruihong Zhang

Sujuan Zhi

Lanlan Liu

Xuyue Liu

Xiaoning Feng

Yanru Chen

Xiaoli Zhang

Jing Hao

Affiliations

Soon will be listed here.

Abstract

Background: Renal cell carcinoma is the most common malignant tumor of the kidney. The 5-year survival of renal cell carcinoma with distant metastasis is very low. Sohlh2 is a newly discovered tumor suppressor gene playing inhibitory roles in a variety of tumors, but its role in renal cell carcinoma has not been reported.

Methods: To clarify the role of Sohlh2 in the occurrence and development of renal cell carcinoma, we constructed stably transfected human renal cell carcinoma cell lines with Sohlh2 overexpression and Sohlh2 knockdown, separately. First, we studied the effects of Sohlh2 on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of renal cell carcinoma cells and . Then, we detected whether Sohlh2 functions through DNMT3a/Klotho using Western blotting, qPCR, and Cell Counting Kit-8 (CCK-8) assay. Finally, we collected 40 resected renal cell carcinoma samples to study the relevance between Sohlh2, DNMT3a, and Klotho by immunohistochemistry.

Results: Our results showed that Sohlh2 was downregulated in renal cell carcinoma, and its expression level was negatively correlated with tumor staging. Both and experiments confirmed that Sohlh2 overexpression inhibited the proliferation, migration, invasion, metastasis, and EMT of renal cell carcinoma. Sohlh2 functions through demethylation of Klotho by downregulating the expression of DNA methyltransferase of DNMT3a. In renal cell carcinoma, Sohlh2 was positively correlated with Klotho and negatively correlated with DNMT3a.

Conclusion: Sohlh2 functions as a tumor suppressor gene in renal cell carcinoma by demethylation of Klotho DNMT3a. Sohlh2 correlated with Klotho positively and with DNMT3a negatively in renal cell carcinoma. Our study suggests that Sohlh2 and DNMT3a/Klotho can be used as potential targets for the clinical treatment of renal cell carcinoma.

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References

Acar O, Sanli O . Surgical Management of Local Recurrences of Renal Cell Carcinoma. Surg Res Pract. 2016; 2016:2394942. PMC: 4746394. DOI: 10.1155/2016/2394942. View

Yu L, Huang S, Lv W, He Z, Hu J . [Research Progress of the Role of EMT in EGFR-TKIs Resistance  of Non-small Cell Lung Cancer]. Zhongguo Fei Ai Za Zhi. 2018; 21(12):907-911. PMC: 6318572. DOI: 10.3779/j.issn.1009-3419.2018.12.08. View

Jonasch E, Gao J, Rathmell W . Renal cell carcinoma. BMJ. 2014; 349:g4797. PMC: 4707715. DOI: 10.1136/bmj.g4797. View

Ruan H, Yang H, Wei H, Xiao W, Lou N, Qiu B . Overexpression of SOX4 promotes cell migration and invasion of renal cell carcinoma by inducing epithelial-mesenchymal transition. Int J Oncol. 2017; 51(1):336-346. DOI: 10.3892/ijo.2017.4010. View

Mosa O, Skitek M, Jerin A . Validity of Klotho, CYR61 and YKL-40 as ideal predictive biomarkers for acute kidney injury: review study. Sao Paulo Med J. 2016; 135(1):57-65. PMC: 9969721. DOI: 10.1590/1516-3180.2016.0099220516. View

Moore L, Le T, Fan G . DNA methylation and its basic function. Neuropsychopharmacology. 2012; 38(1):23-38. PMC: 3521964. DOI: 10.1038/npp.2012.112. View

Choi Y, Yuan D, Rajkovic A . Germ cell-specific transcriptional regulator sohlh2 is essential for early mouse folliculogenesis and oocyte-specific gene expression. Biol Reprod. 2008; 79(6):1176-82. PMC: 2780471. DOI: 10.1095/biolreprod.108.071217. View

Mencke R, Olauson H, Hillebrands J . Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies. Adv Drug Deliv Rev. 2017; 121:85-100. DOI: 10.1016/j.addr.2017.07.009. View

Joseph J, Harishankar M, Pillai A, Devi A . Hypoxia induced EMT: A review on the mechanism of tumor progression and metastasis in OSCC. Oral Oncol. 2018; 80:23-32. DOI: 10.1016/j.oraloncology.2018.03.004. View

10.

Gao Y, Li H, Ma X, Fan Y, Ni D, Zhang Y . KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1. Cancer Res. 2016; 77(2):330-342. DOI: 10.1158/0008-5472.CAN-16-0348. View

11.

Zhou J, Wang T, Qiu T, Chen Z, Ma X, Zhang L . Ubiquitin-specific protease-44 inhibits the proliferation and migration of cells via inhibition of JNK pathway in clear cell renal cell carcinoma. BMC Cancer. 2020; 20(1):214. PMC: 7068999. DOI: 10.1186/s12885-020-6713-y. View

12.

Li M, Wang Y, Song Y, Bu R, Yin B, Fei X . Aberrant DNA methyltransferase 1 expression in clear cell renal cell carcinoma development and progression. Chin J Cancer Res. 2014; 26(4):371-81. PMC: 4153934. DOI: 10.3978/j.issn.1000-9604.2014.08.03. View

13.

Wang Z, Zhang Y . [Metabonome in Early Diagnosis of Renal Cell Carcinoma]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2019; 41(5):709-713. DOI: 10.3881/j.issn.1000-503X.10957. View

14.

Rasmussen F . Metastatic renal cell cancer. Cancer Imaging. 2013; 13(3):374-80. PMC: 3783114. DOI: 10.1102/1470-7330.2013.9035. View

15.

Chen B, Wang X, Zhao W, Wu J . Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res. 2010; 29:99. PMC: 2912837. DOI: 10.1186/1756-9966-29-99. View

16.

Jiangqiao Z, Tao Q, Zhongbao C, Xiaoxiong M, Long Z, Jilin Z . Anti-silencing function 1B histone chaperone promotes cell proliferation and migration via activation of the AKT pathway in clear cell renal cell carcinoma. Biochem Biophys Res Commun. 2019; 511(1):165-172. DOI: 10.1016/j.bbrc.2019.02.060. View

17.

Xu Y, Ma Y, Liu X, Gao S . miR‑133b affects cell proliferation, invasion and chemosensitivity in renal cell carcinoma by inhibiting the ERK signaling pathway. Mol Med Rep. 2020; 22(1):67-76. PMC: 7248518. DOI: 10.3892/mmr.2020.11125. View

18.

Liu Q, Yu L, Feng J, Sun Q, Li S, Ye J . The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis. Dis Markers. 2019; 2019:6468729. PMC: 6589248. DOI: 10.1155/2019/6468729. View

19.

Lea-Henry T, Carland J, Stocker S, Sevastos J, Roberts D . Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles. Clin J Am Soc Nephrol. 2018; 13(7):1085-1095. PMC: 6032582. DOI: 10.2215/CJN.00340118. View

20.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View