Epigenetic activation of LY6K predicts the presence of metastasis and poor prognosis in breast carcinoma

Abstract

The role of lymphocyte antigen 6 complex, locus K (LY6K) in breast cancer has been studied, whereas the epigenetic control of LY6K transcription is not fully understood. Here, we report that breast cancer patients with increased LY6K expression had shorter disease-free and overall survival than the patients with low levels of LY6K by multivariate analysis. LY6K also was upregulated in breast cancer patients with distant metastases than those without distant metastases, downregulating E-cadherin expression. Furthermore, xenograft tumor volumes from LY6K knockdown nude mice were reduced than those of mice treated with control lentivirus. Interestingly, LY6K has a CpG island (CGI) around the transcription start site and non-CGI in its promoter, called a CGI shore. LY6K expression was inversely correlated with methylation in not only CGI but CGI shore, which are associated with histone modifications. Additionally, LY6K methylation was increased by the PAX3 transcription factor due to the SNP242 mutation in LY6K CGI shore. Taken together, breast cancer risk and metastasis were significantly associated with not only LY6K expression, but also methylation of CGI shore which induced by SNP242 mutation. Our results suggest that an understanding epigenetic mechanism of the LY6K gene may be useful to diagnose carcinogenic risk and predict outcomes of patients with metastatic breast cancer.

MiR-500a-3p inhibits cell proliferation and invasion by targeting lymphocyte antigen 6 complex locus K (LY6K) in human non-small cell lung cancer

“…Previous researchers support our work in their illustration that LY6K over-expression in xenograft tumors is associated with distant metastasis and survival rate, and that LY6K knockdown significantly slows tumor development [28]. Studies also show that LY6K promotes aggressive features in NSCLC and ESCC and that it is therefore a promising therapeutic target at the molecular level [6].…”

Transgenic overexpression of human LY6K in mice suppresses mature T cell development in the thymus

“…In our previous study, Ly6K expression was identified to be inversely associated with estrogen receptor α (ERα) levels, suggesting that high expression of Ly6K may result in tamoxifen resistance of cancer cells (31). Furthermore, it was recently reported that Ly6K/E signaling involving transforming growth factor β promotes cancer progression and drug resistance in breast cancer (14). Therefore, Ly6K is considered to be both a prognostic marker and a therapeutic target in cancer, particularly in breast cancer (14), and a number of studies have been conducted on the molecular mechanism of LY6K in vitro.…”

“…Furthermore, it was recently reported that Ly6K/E signaling involving transforming growth factor β promotes cancer progression and drug resistance in breast cancer (14). Therefore, Ly6K is considered to be both a prognostic marker and a therapeutic target in cancer, particularly in breast cancer (14), and a number of studies have been conducted on the molecular mechanism of LY6K in vitro. However, the in vivo mechanism of LY6K has received little attention.…”

“…Previous studies have demonstrated that uPARs are generally upregulated in cancer cells and during other inflammatory conditions or infections, and this makes them attractive therapeutic targets for the impairment of ECM-cell interactions and the signaling pathways of abnormal cells (1,(7)(8)(9) Lymphocyte antigen 6 family member K (Ly6K) is a recently discovered member of the uPAR family and was first identified as a molecular marker for head-and-neck squamous cell carcinoma (10). Previous studies have demonstrated that Ly6K is upregulated in numerous types of cancer, including esophageal squamous cell carcinoma, bladder cancer and breast cancer, and contributes to cell growth, migration, invasion, and immune escape (11)(12)(13)(14). In breast cancer, it is reported that Ly6K expression is regulated by the transcription factor activator protein-1, and that Ly6K promotes cell proliferation and metastasis by activating the Raf-1/MEK/ERK signaling pathway in cancer (15).…”

Small Molecule Binds with Lymphocyte Antigen 6K to Induce Cancer Cell Death

“…Recently, it has been shown that genes other than Myc on 8q24 play an important role in cancer progression [5]. High expression of LY6K mRNA is associated with poor survival outcomes in an array of solid cancers, including cervical, breast, head and neck, bladder, esophageal, lung, and colorectal cancer [6][7][8][9][10]. The expression of LY6K in normal cells is mainly found in testicular germ cells, where it plays a role in sperm cell migration [11].…”