ERa-induced m6A reader HNRNPC maintains DDX6 mRNA stability to promote tumor progression in ER+BC.

BACKGROUND: Breast cancer (BC) remains a major threat to women's health globally. The RNA m6A modification and its readers, such as heterogeneous nuclear ribonucleoprotein C (HNRNPC), which is upregulated in multiple cancers, play critical roles in tumorigenesis. METHODS: We assessed gene/protein expression (RT-qPCR, western blot) and cellular functions. Molecular mechanisms involving HNRNPC, DDX6, and m6A modifications were deciphered using RIP, meRIP, ChIP, and RNA pull-down assays. The oncogenic role of HNRNPC was confirmed in xenograft models. RESULTS: We found that HNRNPC has an abnormally high expression in BC, and knocking down HNRNPC could inhibit the tumor progression of BC. RNA immunoprecipitation revealed that HNRNPC could recognize and bind to the continuous "U" region in 3'UTR of m6A-modified DEAD-Box helicase 6 (DDX6) in the nucleus, which maintains the stability of DDX6 mRNA. Besides, estrogen receptor (ER) α could serve as a transcription factor and bind to the promoter site of HNRNPC, which up-regulated HNRNPC expression. DISCUSSION: We unveiled an ERα/HNRNPC/DDX6 axis in ER+ breast cancer, wherein ERα transcriptionally upregulates HNRNPC, which in turn stabilizes DDX6 mRNA in an m6A-dependent manner to drive tumor progression, suggesting HNRNPC as a promising therapeutic target.