Identification of the m6A RNA Methylation Regulators WTAP as a Novel Prognostic Biomarker and Genomic Alterations in Cutaneous Melanoma

Abstract

Background: The purpose of our research was to establish a gene signature and determine the prognostic value of m6A methylation regulators in cutaneous melanoma and WTAP as a protective gene in cutaneous melanoma prognosis, we also evaluated gene mutations in cutaneous melanoma.Methods: We downloaded the RNA-seq transcriptome data and the clinical information for cutaneous melanoma patients from the GTEx and TCGA databases. Consensus clustering analysis was applied to divide the samples into two groups. Then the least absolute shrinkage and selection operator (LASSO) analyses were conducted to construct a risk signature, and we use external and internal datasets to verify its predictive value. We further searched the cBioPortal tools to detect genomic alterations and WTAP mutations. Finally, WTAP was further identified as a prognostic factor, and the related mechanisms mediated by WTAP were predicted by gene set enrichment analysis (GSEA). Experimental validations and have been further carried out.Results: Notably, m6A RNA methylation regulators play significant roles in tumorigenesis and development. In total, we selected three subtypes of cutaneous melanoma according to consensus clustering of the m6A RNA methylation regulators, and the stage of cutaneous melanoma was proven to be related to the subtypes. The Cox regression and LASSO analyses built a risk signature including ELF3, ZC3H13 and WTAP. The prognostic value of the risk signature in internal and external datasets have been proven then. The whole-genome and selected gene WTAP mutations were further explored. WTAP as a single prognostic factor was also explored and found to serve as an independent protective prognostic factor.Conclusions: Our study constructed a stable risk signature composed of m6A RNA methylation regulators in cutaneous melanoma. Moreover, WTAP was identified as a valuable prognostic factor and potential molecular target for cutaneous melanoma treatment.

Research Progress of RNA Methylation Modification in Colorectal Cancer

“…The third writer protein WTAP has been shown to have tumor-promoting action in many malignancies, including liver cancer, gastric cancer and osteosarcoma ( Chen et al, 2019a ; Li et al, 2020a ; Chen et al, 2020c ; Zhou et al, 2021b ; Feng et al, 2021 ). In colorectal cancer, studies have pointed out WTAP is also oncogenic and can promote the progression of colorectal cancer through the WTAP/WT1/TBL1 axis in the canonical Wnt signaling pathway ( Zhang et al, 2016a ).…”

Comprehensive analysis about prognostic and immunological role of WTAP in pan-cancer

“…However, some studies suggest that WTAP may sometimes play a protective role. WTAP were down-regulated in lung adenocarcinoma, ( Li et al, 2020b ), and it was a protective gene in cutaneous melanoma prognosis ( Feng et al, 2021 ). In addition, WTAP was essential for the tumor-suppressor function of carbonic anhydrase 4 (CA4) in colon cancer ( Zhang et al, 2016 ).…”

“…That is to say, with the increase of expression, the incidence of tumors increases significantly. While for lung cancer (Li et al, 2020a;Gu et al, 2021), melanoma (Feng et al, 2021), the result is exactly the opposite, high expression of WTAP is a protective factor. With the high expression of WTAP, the incidence of tumors decreases.…”

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

“…Epigenetic alterations enable more rapid and reversible modulation of cellular responses than changes to the coding genome. Melanoma tumorigenesis and progression has been linked to dysregulation of epigenetic mechanisms, such as chromatin remodeling complexes (INO80 [ 59 , 60 ], ISWI [ 61 , 62 ], and SWI/SNF [ 63 , 64 , 65 ]); histone post-translational modifications (PTMs) by histone acetyltransferases (HATs) [ 66 ], deacetylases (HDACs) [ 67 ], methyltransferases (HMTs) [ 68 ], and demethylases (HDMs) [ 69 ]; histone variants [ 70 , 71 , 72 ]; DNA [ 73 , 74 , 75 ] and RNA [ 76 , 77 , 78 ] methylation; plus non-coding [ 79 , 80 , 81 , 82 ], micro- [ 83 , 84 , 85 ], and circular [ 86 , 87 , 88 ] RNA. Unsurprisingly, epigenetic changes are also linked to immune [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ] and targeted [ 98 , 99 , 100 , 101 , 102 , 103 ] therapy resistance.…”