Upregulation of LY6K Induced by FTO-mediated Demethylation Promotes the Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma Via CAV-1-mediated ERK1/2 Signaling Activation

Overview

Journal Histol Histopathol

Specialties Anatomy & Histology
Pathology

Date 2024 Mar 12

PMID 38469708

Authors

Chen Xu

Rujuan Gong

Haibing Yang

Affiliations

Soon will be listed here.

Abstract

Lymphocyte antigen 6 complex locus K (LY6K) has been demonstrated to play a significant role in cancers and identified as a therapeutic biomarker for head and neck squamous cell carcinoma. However, the role of LY6K in oral squamous cell carcinoma (OSCC) has not been explored. The current study discovered that LY6K was aberrantly upregulated in OSCC cell lines and tissues and that high LY6K expression significantly correlated with poorer survival of OSCC patients. Through stable knockdown of LY6K, we found that the growth, colony formation, migration, and invasion of OSCC cells were substantially suppressed. In addition, tumor growth and lung metastasis were effectively inhibited by LY6K depletion. Mechanically, LY6K binds with CAV-1 and activates CAV-1-mediated MAPK/ERK signaling to exert its oncogenic effects on OSCC. In addition, LY6K expression in OSCC was discovered to be regulated by FTO-mediated RNA N6-methyladenosine (mA) modification in an IGF2BP1-dependent manner. Generally, LY6K expression was upregulated by FTO-mediated demethylation in OSCC, which promoted the tumorigenesis and metastasis of OSCC via activating the CAV-1-mediated ERK1/2 signaling pathway.

Citing Articles

Silencing LY6K Suppresses CD44 EpCAM HCT116 Human Colon Cancer Stem Cells Growth: Insights from In Vitro and In Vivo Evidence.

Fu C, Chen K, Duan J, Liu K, Li M, Chen Y Curr Issues Mol Biol. 2024; 46(12):14045-14057.

PMID: 39727968 PMC: 11727511. DOI: 10.3390/cimb46120840.

References

An Y, Duan H . The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 2022; 21(1):14. PMC: 8753874. DOI: 10.1186/s12943-022-01500-4. View

Arellano-Garcia M, Li R, Liu X, Xie Y, Yan X, Loo J . Identification of tetranectin as a potential biomarker for metastatic oral cancer. Int J Mol Sci. 2010; 11(9):3106-21. PMC: 2956083. DOI: 10.3390/ijms11093106. View

Bau D, Tsai M, Tsou Y, Wang C, Tsai C, Sun S . The association of Caveolin-1 genotypes with oral cancer susceptibility in Taiwan. Ann Surg Oncol. 2011; 18(5):1431-8. DOI: 10.1245/s10434-010-1483-4. View

Benti S, Tiwari P, Goodlett D, Daneshian L, Kern G, Smith M . Small Molecule Binds with Lymphocyte Antigen 6K to Induce Cancer Cell Death. Cancers (Basel). 2020; 12(2). PMC: 7072568. DOI: 10.3390/cancers12020509. View

Carrero I, Liu H, Sikora A, Milosavljevic A . Histoepigenetic analysis of HPV- and tobacco-associated head and neck cancer identifies both subtype-specific and common therapeutic targets despite divergent microenvironments. Oncogene. 2019; 38(19):3551-3568. PMC: 6756123. DOI: 10.1038/s41388-018-0659-4. View

Cheng Y, Chen J, Shi Y, Fang X, Tang Z . MAPK Signaling Pathway in Oral Squamous Cell Carcinoma: Biological Function and Targeted Therapy. Cancers (Basel). 2022; 14(19). PMC: 9563402. DOI: 10.3390/cancers14194625. View

van Dongen G, Smeets S, Nieuwenhuis E, Stigter-van Walsum M, Snow G, Brakenhoff R . Characterization of the human Ly-6 antigens, the newly annotated member Ly-6K included, as molecular markers for head-and-neck squamous cell carcinoma. Int J Cancer. 2003; 103(6):768-74. DOI: 10.1002/ijc.10903. View

Degen M, Natarajan E, Barron P, Widlund H, Rheinwald J . MAPK/ERK-dependent translation factor hyperactivation and dysregulated laminin γ2 expression in oral dysplasia and squamous cell carcinoma. Am J Pathol. 2012; 180(6):2462-78. PMC: 3378915. DOI: 10.1016/j.ajpath.2012.02.028. View

Feng J, Xu J, Xu Y, Xiong J, Xiao T, Jiang C . CLIC1 promotes the progression of oral squamous cell carcinoma via integrins/ERK pathways. Am J Transl Res. 2019; 11(2):557-571. PMC: 6413291. View

10.

Fu X, Feng Y . QKI-5 suppresses cyclin D1 expression and proliferation of oral squamous cell carcinoma cells via MAPK signalling pathway. Int J Oral Maxillofac Surg. 2014; 44(5):562-7. DOI: 10.1016/j.ijom.2014.10.001. View

11.

Fujihara Y, Miyata H, Ikawa M . Factors controlling sperm migration through the oviduct revealed by gene-modified mouse models. Exp Anim. 2018; 67(2):91-104. PMC: 5955741. DOI: 10.1538/expanim.17-0153. View

12.

Guan X, Wang N, Cui F, Liu Y, Liu P, Zhao J . Caveolin-1 is essential in the differentiation of human adipose-derived stem cells into hepatocyte-like cells via an MAPK pathway-dependent mechanism. Mol Med Rep. 2016; 13(2):1487-94. PMC: 4732856. DOI: 10.3892/mmr.2015.4743. View

13.

Huang G, Wu Q, Zheng Z, Shao T, Chen Y, Zeng W . M6A-related bioinformatics analysis reveals that HNRNPC facilitates progression of OSCC via EMT. Aging (Albany NY). 2020; 12(12):11667-11684. PMC: 7343469. DOI: 10.18632/aging.103333. View

14.

Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, Ito H . Cancer-testis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res. 2007; 67(24):11601-11. DOI: 10.1158/0008-5472.CAN-07-3243. View

15.

Jaafari-Ashkavandi Z, Aslani E . Caveolin-1 expression in oral lichen planus, dysplastic lesions and squamous cell carcinoma. Pathol Res Pract. 2017; 213(7):809-814. DOI: 10.1016/j.prp.2017.03.006. View

16.

Jiang Y, Krantz S, Qin X, Li S, Gunasekara H, Kim Y . Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy. Redox Biol. 2022; 52:102304. PMC: 9018165. DOI: 10.1016/j.redox.2022.102304. View

17.

Kaya S, Wiesmann N, Goldschmitt J, Kruger M, Al-Nawas B, Heider J . Differences in the expression of caveolin-1 isoforms in cancer-associated and normal fibroblasts of patients with oral squamous cell carcinoma. Clin Oral Investig. 2021; 25(10):5823-5831. PMC: 8443514. DOI: 10.1007/s00784-021-03887-8. View

18.

Keinanen A, Uittamo J, Marinescu-Gava M, Kainulainen S, Snall J . Preoperative C-reactive protein to albumin ratio and oral health in oral squamous cell carcinoma patients. BMC Oral Health. 2021; 21(1):132. PMC: 7977568. DOI: 10.1186/s12903-021-01516-0. View

19.

Kim Y, Park S, Lee Y, Kong H, Park J . miRNAs involved in LY6K and estrogen receptor α contribute to tamoxifen-susceptibility in breast cancer. Oncotarget. 2016; 7(27):42261-42273. PMC: 5173133. DOI: 10.18632/oncotarget.9950. View

20.

Kong H, Park S, Kim Y, Kim K, Lee H, Kang H . Epigenetic activation of LY6K predicts the presence of metastasis and poor prognosis in breast carcinoma. Oncotarget. 2016; 7(34):55677-55689. PMC: 5342445. DOI: 10.18632/oncotarget.10972. View