The dynamic regulation of RNA N6-methyladenosine (m6A) modification is decisive for tumor initiation, metastasis and recurrence. Whereas, the underlying mechanism that downstream signal regulated by FTO to control breast cancer development through m6A modification needs to be further studied. In this study, we used m6A methylation and RNA sequencing (seq) to verify the role of FTO and its downstream signal in the development of breast cancer. Here, we found that FTO was abnormally expressed in breast cancer and crucial for breast cancer development. Mechanistically, FTO inhibited CYP27B1 mRNA stability through an m6A-HNRNPC dependent manner, subsequently reduced 1,25D3 synthesis, and activated STAT3 signaling pathway; p-STAT3 further activated the transcription of FTO, which forming a positive feedback loop to promote BC development. Interestingly, the increasing of 1,25D3 synthesis induced by FTO knockdown further inhibited FTO transcription through VDR, thereby reducing the development of BC.Especially, pharmacologic inhibition of FTO suppressed tumor growth,which combined with chemotherapy, synergistically eliminated tumor growth and increased chemosensitivity in xenografted tumor in vivo. Our findings emphasized the essential role of FTO/CYP27B1/1,25D3 axis for promoting breast cancer development and providing theoretical basis for finding effective therapeutic methods.
Keywords: 1,25-dihydroxyvitamin D3; CYP27B1; Chemotherapy resistence; FTO; m6A modification.
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