Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer

Abstract

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.

DUSP5 regulated by YTHDF1-mediated m6A modification promotes epithelial-mesenchymal transition and EGFR-TKI resistance via the TGF-β/Smad signaling pathway in lung adenocarcinoma

“…TCGA has identified links between DNA methylation and gene expression through the use of MEXPRESS (https://mexpress.be/) [30] and SMART (http://www.bioinfo-zs.com/smartapp/) [31]. The MethPrimer software [32] was used to predict cytosine-phosphate-guanine (CpG) islands (CGIs) in the sequences of gene promoters.…”

MHC class III lymphocyte antigens 6 as endogenous immunotoxins: Unlocking immunotherapy in proficient mismatch repair colorectal cancer

“…In CRC, LY6G6D promoter results hypomethylated in pMMR while its hypermethylation persists or increases in dMMR cancers or with mucinous subtype. This suggests that LY6G6D is a potent tissue damage response molecule under the control of epigenetic and inflammatory pathways (Caruso et al, 2022). LY6G6D is an excellent tumor-associated antigen that exhibits large differential expression between normal and CRC, predominantly in pMMR CRC refractory to immunotherapy (Hermel & Sigal, 2019) (Figure 3b,c).…”

“…Coupling these with computational approaches developed to analyze and interpret such data has led to the knowledge that many human MHC‐III LY6G genes are not expressed in leukocytes and nonimmune cell lines. Rare exception can be found for LY6G6F, which is expressed in Macrophages, and for LY6G6D and LY6G6C which are expressed in Squamous epithelial cells and in Syncytiotrophoblasts (Caruso et al, 2022; Wang et al, 2019). The expression of MHC‐III markers in syncytiotrophoblasts reduces the risk of a T‐cell‐mediated attack by the maternal immune system.…”

“…The tumor‐associated overexpression of LY6G6D was identified by a transcriptomic screening of 6000 immune‐related genes across a variety of cancer types. Interestingly, LY6G6D expression is extremely limited in healthy normal tissues as consequence of promoter hyper‐methylation (Caruso et al, 2022) (Figure 3a). In CRC, LY6G6D promoter results hypomethylated in pMMR while its hypermethylation persists or increases in dMMR cancers or with mucinous subtype.…”

Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis

“…These results suggest that the vast majority of gene expression changes manifest in the early stages of the CRC development [ 24 , 25 ] and support the necessity to investigate precancerous lesions and early CRC. There are numerous genome wide and high-throughput analyses investigating expression and/or methylation status of CRC in comparison to the normal mucosa [ 22 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Publications investigating colorectal adenoma to adenocarcinoma and normal mucosa were in the past mainly focused on proteomic analyses and more recently mainly on the serum and plasma expression profiling from CRC patients [ 29 , 34 , 35 ].…”