N6 -Methyladenosine Regulates mRNA Stability and Translation Efficiency of KRT7 to Promote Breast Cancer Lung Metastasis

Abstract

The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them as BC^LMF3 cells. In these cells, mRNA N⁶ -methyladenosine (m⁶A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m⁶A-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m⁶A promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7. SIGNIFICANCE: This study suggests that N⁶ -methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.