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

Ming Zhang1,2, Jue Wang3, Yucui Jin1

  • 1Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, 211166, Nanjing, P.R. China.

British Journal of Cancer
|October 10, 2022
PubMed
Abstract

Insights

Long non-coding RNA FGF14-AS2 inhibits breast cancer bone metastasis by suppressing osteoclast formation. This lncRNA may serve as a prognostic biomarker and therapeutic target for breast cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Long non-coding RNA (lncRNA) FGF14-AS2 is recognized as a suppressor of breast cancer (BCa) metastasis.
  • The specific role of FGF14-AS2 in the bone metastasis of BCa has not been previously elucidated.

Purpose of the Study:

  • To investigate the function of FGF14-AS2 in breast cancer bone metastasis.
  • To elucidate the underlying molecular mechanisms of FGF14-AS2 action in BCa bone metastasis.
  • To evaluate the clinical significance of FGF14-AS2 as a prognostic biomarker in BCa.

Main Methods:

  • In vitro and in vivo assays, including TRAP assay and intratibial injection, were used to assess FGF14-AS2's role in BCa bone metastasis.
  • Polyribosome profiling, RNA pulldown with LC/MS, RIP, dual-luciferase, and Co-IP assays were employed to identify and validate molecular interactions.
  • Kaplan-Meier Plotter was utilized to analyze the prognostic value of FGF14-AS2 expression in BCa patients.

Main Results:

  • FGF14-AS2 was found to suppress osteoclast differentiation and osteolytic metastasis of BCa.
  • Mechanistically, FGF14-AS2 inhibits RUNX2 translation by interfering with the eIF4E/eIF4G complex and eIF4E phosphorylation, thereby reducing RANKL transcription.
  • FGF14-AS2 downregulation occurs via YTHDF2-mediated RNA degradation in an m6A-dependent manner. High YTHDF2 and low FGF14-AS2 expression correlated with worse distant metastasis-free survival (DMFS).

Conclusions:

  • FGF14-AS2 plays a critical role in suppressing osteolytic metastasis in breast cancer.
  • FGF14-AS2 demonstrates potential as a prognostic biomarker for BCa bone metastasis.
  • FGF14-AS2 represents a promising therapeutic target for managing BCa bone metastasis.

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