Epitranscriptomic Regulation of Platinum Resistance via the METTL3-ADAM23 Axis in Ovarian Cancer

TL;DR

The study finds that METTL3 and ADAM23 are linked in platinum-resistant ovarian cancer, suggesting that targeting METTL3 could improve treatment outcomes.

Contribution

The discovery of a novel METTL3-ADAM23 regulatory axis in platinum resistance in ovarian cancer.

Findings

METTL3 and m6A RNA methylation increase in platinum-resistant ovarian cancer models.

Pharmacologic inhibition of METTL3 enhances platinum responsiveness in ovarian cancer cells.

ADAM23 is identified as a METTL3-regulated transcript associated with platinum response.

Abstract

What are the main findings?
METTL3 expression and global m6A RNA methylation are increased following platinum treatment and in platinum-resistant ovarian cancer models.ADAM23 is identified as a METTL3-regulated, m6A-associated transcript whose expression correlates with platinum response.

METTL3 expression and global m6A RNA methylation are increased following platinum treatment and in platinum-resistant ovarian cancer models.

ADAM23 is identified as a METTL3-regulated, m6A-associated transcript whose expression correlates with platinum response.

What is the implication of the main finding?
METTL3-dependent epitranscriptomic regulation is associated with the development of platinum resistance in ovarian cancer.Pharmacologic inhibition of METTL3 enhances platinum responsiveness, supporting m6A regulation as a potential therapeutic vulnerability.

METTL3-dependent epitranscriptomic regulation is associated with the development of platinum resistance in ovarian cancer.

Pharmacologic inhibition of METTL3 enhances platinum responsiveness, supporting m6A regulation as a potential therapeutic vulnerability.

N6-methyladenosine (m6A) has emerged as a pivotal regulator of post-transcriptional gene control, yet its contribution to chemotherapy resistance remains insufficiently defined. Here, we describe a previously unrecognized METTL3-ADAM23 epitranscriptomic regulatory relationship associated with platinum (Pt) resistance in ovarian cancer (OC). We show that cisplatin treatment increases global m6A levels and METTL3 expression, linking Pt exposure to activation of the m6A machinery. Functional perturbation studies demonstrate that METTL3 overexpression enhances cisplatin resistance, whereas METTL3 knockdown or pharmacologic inhibition with the selective METTL3 inhibitor STM2457 sensitizes OC cells to Pt treatment in vitro and improves Pt response in vivo. Transcriptomic profiling identifies ADAM23, a cell-adhesion-related tumor suppressor, as a METTL3-dependent, m6A-associated transcript, with altered mRNA expression observed across multiple experimental systems and several high-confidence predicted m6A sites within its transcript. Cisplatin-associated METTL3 upregulation correlates with reduced ADAM23 expression, suggesting a potential regulatory relationship that may contribute to chemoresistance. Together, these findings support a model in which METTL3-associated increases in m6A methylation are linked to Pt resistance, in part through modulation of ADAM23 expression, and highlight METTL3 as a potential therapeutic target in OC.

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