Dissecting the role of RNA modification regulatory proteins in melanoma

Biao Wang,Parmanand Malvi,Shreni Shah,Romi Gupta

doi:10.18632/oncotarget.26959

Biao Wang, Parmanand Malvi + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.26959

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Abstract

Melanoma is the deadliest form of skin cancer. Despite recent advances in medicine and the development of new treatments for melanoma, cures remain elusive as acquired resistance to both targeted and immunotherapies are becoming common. Therefore, more studies are conducted to dissect underlying molecular mechanisms that drive melanoma growth in order to provide better therapeutic option. Here, employing a comprehensive and unbiased analysis of different RNA modification regulatory proteins using various publicly available databases we identify the most relevant RNA modifying proteins that plays crucial role in melanoma development. Our study started with the analysis of various genetic alterations (amplifications, mutations/deletion) as well as RNA overexpression of these RNA modification regulatory proteins in The Cancer Genome Atlas melanoma database. We then analyzed their expression in The Human Protein Atlas data. The result of analysis revealed that only a subset of RNA modification regulatory proteins are overexpressed in >75% of melanoma patient cases as compared to normal skin. However, when examined in Oncomine dataset we found only two genes (METTL4 and DNMT3A) were significantly overexpressed in melanoma samples versus normal skin samples and matched with the results of The Human Protein Atlas data. Therefore, we functionally validated METTL4 and DNMT3A using shRNA-mediated knockdown and found that their knockdown in melanoma cells led to melanoma cells growth inhibition. Collectively, in this study, we investigated the epitranscriptomic landscape of melanoma using various publicly available database and identified DNMT3A and METTL4 as the most relevant potential regulators of melanoma growth.

Highlights

Melanoma is the deadliest form of skin cancer that account for over 80% skin cancer-related death [1]
Analysis of TCGA dataset for N1methyladenosine (m1A), N6-methyladenosine (m6A) and 5-methylcytosine (m5C) RNA modification regulatory proteins in melanoma
Our focus was to analyze RNA modification regulatory proteins that belong to m1A, m6A, m5C, hm5C, inosine and other RNA modifying protein group. m1A modification regulatory proteins consists of writers and erasers. m1A is a reversible modification of tRNA and mRNA

Summary

Introduction

Melanoma is the deadliest form of skin cancer that account for over 80% skin cancer-related death [1]. Among these, activating mutations in BRAF and NRAS gene and inactivating mutations in NF1 gene accounts for over 80% of melanoma and results in the activation of MAP kinase pathway [8, 9]. Based on the findings that MAPK pathway is activated in a large percentage of melanoma, clinically effective BRAF kinase and MEK1/2 kinase inhibitors have been developed and are being used to treat metastatic melanoma patients with BRAF mutations [10, 11]. Even with advances in precision therapy approaches and success of immunotherapies, melanoma remains a difficult disease to treat with less than 10% fiveyear survival rate for patients with lymph node metastasis www.oncotarget.com and less than 5% five-year survival rate for melanoma patients with distant metastasis [18,19,20,21,22]

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