Methylation of Nonessential Genes in Cutaneous Melanoma – Rule Out Hypothesis

Authors

Ivan P Gorlov
Kathleen Conway
Sharon N Edmiston
Eloise A Parrish
Honglin Hao
Christopher I Amos
Spiridon Tsavachidis
Olga Y Gorlova
Colin Begg
Eva Hernando
Chao Cheng
Ronglai Shen
Irene Orlow
Li Luo
Marc S Ernstoff
Pei Fen Kuan
David W Ollila
Yihsuan S Tsai
Marianne Berwick
Nancy E Thomas

Publication Date

6-1-2023

Journal

Melanoma Research

DOI

10.1097/CMR.0000000000000881

PMID

36805567

PMCID

PMC10148896

PubMedCentral® Posted Date

6-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Melanoma, Skin Neoplasms, Promoter Regions, Genetic, DNA Methylation, CpG Islands, Gene Expression Regulation, Neoplastic, Melanoma, Cutaneous Malignant, Methylation, melanoma, gene expression, selective advantage, essential genes, nonessential genes

Abstract

Differential methylation plays an important role in melanoma development and is associated with survival, progression and response to treatment. However, the mechanisms by which methylation promotes melanoma development are poorly understood. The traditional explanation of selective advantage provided by differential methylation postulates that hypermethylation of regulatory 5'-cytosine-phosphate-guanine-3' dinucleotides (CpGs) downregulates the expression of tumor suppressor genes and therefore promotes tumorigenesis. We believe that other (not necessarily alternative) explanations of the selective advantages of methylation are also possible. Here, we hypothesize that melanoma cells use methylation to shut down transcription of nonessential genes - those not required for cell survival and proliferation. Suppression of nonessential genes allows tumor cells to be more efficient in terms of energy and resource usage, providing them with a selective advantage over the tumor cells that transcribe and subsequently translate genes they do not need. We named the hypothesis the Rule Out (RO) hypothesis. The RO hypothesis predicts higher methylation of CpGs located in regulatory regions (CpG islands) of nonessential genes. It also predicts the higher methylation of regulatory CpGs linked to nonessential genes in melanomas compared to nevi and lower expression of nonessential genes in malignant (derived from melanoma) versus normal (derived from nonaffected skin) melanocytes. The analyses conducted using in-house and publicly available data found that all predictions derived from the RO hypothesis hold, providing observational support for the hypothesis.

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