YTHDF2-mediated FGF14-AS2 decay promotes osteolytic metastasis of breast cancer by enhancing RUNX2 mRNA translation

Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons de tissus tumoraux et de tissus adjacents normaux provenant de patientes atteintes d'un cancer du sein, cette étude met en évidence un mécanisme par lequel la dégradation du long ARN non codant FGF14-AS2, induite par la protéine YTHDF2, favorise le développement de métastases ostéolytiques en augmentant la traduction de l'ARN messager du facteur de transcription RUNX2

Résumé en anglais

Background : LncRNA FGF14-AS2 is a critical suppressor in breast cancer (BCa) metastasis. However, whether FGF14-AS2 plays a role in the bone metastasis of BCa remains unknown.

Methods : TRAP assay and intratibial injection were carried out to evaluate the role of FGF14-AS2 in BCa bone metastasis in vitro and in vivo. Polyribosome profiling was done to examine the translation level. RNA pulldown combined with LC/MS was performed to identify the lncRNA-binding partner, RIP, dual-luciferase assay, and Co-IP assays as well to testify these physical interactions. The prognostic value of FGF14-AS2 expression level in BCa patients was analysed using Kaplan–Meier Plotter.

Results : We found that FGF14-AS2 suppresses osteoclast differentiation and osteolytic metastasis of BCa. Mechanistically, FGF14-AS2 suppresses the translation of RUNX2 by inhibiting the assembly of eIF4E/eIF4G complex and the phosphorylation of eIF4E, thereby reducing the transcription of RANKL, an essential regulator of osteoclast differentiation. Moreover, FGF14-AS2 is downregulated by YTHDF2-mediated RNA degradation in an m6A-dependent manner. Clinically, patients with high YTHDF2 and low FGF14-AS2 expression levels showed worse distant metastasis-free survival (DMFS).

Conclusions : FGF14-AS2 plays a crucial role in osteolytic metastasis, and may serve as a promising prognostic biomarker and therapeutic target for BCa bone metastasis.