In addition to being novel
biomarkers for poor
cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to
tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human
cancers. Transcriptome, epigenome and proteomic data from independent
cancer databases were analyzed in silico and validated independently in 334
colorectal cancer tissues (CRC).
RNA mediated gene silencing of regulatory genes, and treatment with
MEK and
p38 MAPK inhibitors were also tested in vitro. We report here that the Lymphocyte
antigen 6G6D is universally downregulated in mucinous CRC, while its activation progresses through the classical
adenoma-
carcinoma sequence. The DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and histological subtypes. Depletion of
DNA methyltransferase 1 (DNMT1), which maintains DNA methylation, results in the derepression of LY6G6D expression.
RNA-mediated gene silencing of p38α MAPK or its selective chemical inhibition, however, reduces LY6G6D expression, reducing
trametinib's anti-inflammatory effects. Patients treated with FOLFOX-based first-line
therapy experienced decreased survival due to hypermethylation of the LY6G6D promoter and decreased p38α MAPK signaling. We found that
cancer-specific
immunodominant epitopes are controlled by p38α MAPKs signaling and suppressed by DNA methylation in histological variants with Mucinous differentiation. This work provides a promising prospective for clinical application in diagnosis and personalized therapeutic strategies of
colorectal cancer.