The Regulatory Mechanism Of Human Ly6k Related To Carcinogenesis And Metastasis In Breast Cancer

The human lymphocyte antigen 6 complex locus K (LY6K) belongs to the lympocyte antigen 6/urokinase-type plasminogen activator receptor (Ly-6/uPAR) superfamily which are associated with development of the immune system and carcinogenesis. LY6K is a cancer biomarker and a therapeutic target that induces invasion and metastasis by activating the Raf-1/MEK/ERK signaling pathway and that stimulates cytotoxic T lymphocytes. However, the molecular mechanisms including genetic and epigenetic that determine human LY6K transcription are complete unknown. To elucidate the genetic mechanisms involved in human LY6K gene regulation and expression, multiple cis elements were predicted using TRANSFAC software, and the LY6K regulatory region was identified using the lucifearse assay in the human LY6K gene promoter. We performed chromatin immunoprecipitation, electrophoretic mobility shift analysis, and supershift assays to investigate the transcription factor activity on the LY6K promoter, and the effect of a single nucleotide polymorphism (SNP) and CpG site methylation on AP-1 transcription factor binding affinity. AP-1 and the CREB transcription factor bound to LY6K promoter within -550/-1, which was essential for LY6K expression but only the AP-1 heterodimer, JunD and Fra-1, modulates LY6K gene transcriptional level. A decrease in LY6K was associated with the SNP242 C allele, a polymorphic G/C-SNP at the 242 nucleotide in the LY6K promoter region (rs2585175), or methylation of the CpG site, which was closely located with the AP-1 site by interfering with binding of the AP-1 transcription factor to the LY6K promoter. In summary, AP-1 activation is important role in promoting LY6K gene expression that regulates cell mobility of breast cancer cells, whereas the SNP242 C allele or methylation of the CpG site may reduce the risk of invasion or metastasis by interfering AP-1 activation. And DNA methylation and histone modification in the 5’-flanking region of the LY6K gene plays an important role in LY6K expression in both breast cancer cells and breast cancer. An understanding of genetic and epigenetic changes in LY6K may contribute to the diagnosis of carcinogenic risk and to an enhanced prediction of outcome in patients with breast cancer. Citation Format: Hyun Kyung Kong, Da Som Son, Jong Hoon Park. The regulatory mechanism of human LY6K related to carcinogenesis and metastasis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2926.