The LncRNAMALAT1-WTAP Axis: a Novel Layer of EMT Regulation in Hypoxic Triple-negative Breast Cancer

Overview

Journal Cell Death Discov

Date 2024 Jun 11

PMID 38862471

Authors

Martina Dragonetti

Chiara Turco

Anna Benedetti

Frauke Goeman

Mattia Forcato

Stefano Scalera

Matteo Allegretti

Gabriella Esposito

Francesco Fazi

Giovanni Blandino

Sara Donzelli

Giulia Fontemaggi

Affiliations

Soon will be listed here.

Abstract

Early metastatic disease development is one characteristic that defines triple-negative breast cancer (TNBC) as the most aggressive breast cancer (BC) subtype. Numerous studies have identified long non-coding RNAs (lncRNA) as critical players in regulating tumor progression and metastasis formation. Here, we show that MALAT1, a long non-coding RNA known to promote various features of BC malignancy, such as migration and neo angiogenesis, regulates TNBC cell response to hypoxia. By profiling MALAT1-associated transcripts, we discovered that lncRNA MALAT1 interacts with the mRNA encoding WTAP protein, previously reported as a component of the N6-methyladenosine (m6A) modification writer complex. In hypoxic conditions, MALAT1 positively regulates WTAP protein expression, which influences the response to hypoxia by favoring the transcription of the master regulators HIF1α and HIF1β. Furthermore, WTAP stimulates BC cell migratory ability and the expression of N-Cadherin and Vimentin, hallmarks of epithelial-to-mesenchymal transition (EMT). In conclusion, this study highlights the functional axis comprising MALAT1 and WTAP as a novel prognostic marker of TNBC progression and as a potential target for the development of therapeutic approaches for TNBC treatment.

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