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

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 mA-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.