METTL3 potentiates resistance to cisplatin through m ⁶ A modification of TFAP2C in seminoma

Abstract

Testicular germ cell tumours (TGCTs) rank as the most common malignancy in men aged 20-34 years, and seminomas are the most type of TGCTs. As a crucial anti-tumour agent with explicit toxicity, cisplatin may render resistance through intertwined mechanisms, even in disease entities with high curative ratio, such as seminoma. Previously, we established cisplatin-resistant seminoma TCam-2 (TCam-2/CDDP) cells and showed that epigenetic regulations, such as non-coding RNA (ncRNA) interactions, might orchestrate cell fate decisions in the cisplatin treatment context in seminoma. N6-methyladenosine (m6A) is the most prevalent internal modification in mRNA. In the present study, we assessed cisplatin resistance in seminoma from the perspective of m⁶ A, another manner of epigenetic modification. The global m⁶ A enrichment of TCam-2 and TCam-2/CDDP was depicted. Then, we elucidated whether transcription factor-activating enhancer-binding protein 2C (TFAP2C) was functionally m⁶ A-modified by methyltransferase-like protein 3 (METTL3), which acted as an m⁶ A 'writer', and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which acted as an m⁶ A 'reader'. Enhanced stability of TFAP2C mRNA promoted seminoma cell survival under cisplatin treatment burden probably through up-regulation of DNA repair-related genes. Hopefully, this study will help improve our understanding of the subtleties of the tumour cellular coping strategy in response to chemotherapy. Targeting factors that are involved in m⁶ A methylation may be an effective strategy for circumventing cisplatin resistance in seminoma.