Abstract
m6A modification is one of the most important post-transcriptional modifications in RNA and plays an important role in promoting translation or decay of RNAs. The role of m6A modifications has been highlighted by increasing evidence in various cancers, which, however, is rarely explored in acral melanoma. Here, we demonstrated that m6A level was highly elevated in acral melanoma tissues, along with the expression of METTL3, one of the most important m6A methyltransferase. Besides, higher expression of METTL3 messenger RNA (mRNA) correlated with a higher stage in primary acral melanoma patients. Knockdown of METTL3 decreased global m6A level in melanoma cells. Furthermore, METTL3 knockdown suppressed the proliferation, migration, and invasion of melanoma cells. In METTL3 knockdown xenograft mouse models, we observed decreased volumes and weights of melanoma tissues. Mechanistically, we found that METTL3 regulates certain m6A-methylated transcripts, thioredoxin domain containing protein 5 (TXNDC5), with the confirmation of RNA-seq, MeRIP-seq, and Western blot. These data suggest that METTL3 may play a key role in the progression of acral melanoma, and targeting the m6A dependent-METTL3 signaling pathway may serve as a promising therapeutic strategy for management of patients of acral melanomas.
Highlights
Melanoma represents the most invasive skin cancer type and comprises the most skin cancerrelated deaths [1]
We found that the imbalance of global m6A abundance and dysregulated expressions of m6A regulators were frequent in primary acral melanoma patients
A375 and SK-MEL-28 were derived from cutaneous melanoma, A875 was derived from melanoma brain metastasis tissue, A2058 and MV3 were derived from metastatic lymph node, and HMY-1 was derived from acral melanoma
Summary
Melanoma represents the most invasive skin cancer type and comprises the most skin cancerrelated deaths [1]. It has distinct clinicopathological subtypes with biological heterogeneity [2]. The. METTL3 Promotes Acral Melanoma Progression previous study revealed that the progression of AM has distinct clinical and genetic features, potentially due to diagnosis at a more advanced clinical stage, or due to biological differences favoring tumor aggression, AM usually has poorer prognosis than other types of cutaneous melanoma [4,5,6]. In recent years, targeted therapies and checkpoint immunotherapies have greatly improved the prognosis of advanced melanomas [7, 8]. Targeting epigenetic regulation represents a novel approach for AM treatment
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