Qin Yilu, Zeng Huan, Dong Zihe, Zhu Chuanlin, Bian Qing, Zhai Xiuming, Tang Hejun, Zhou Fangzhu, Yang Liping, Zhang Juan
Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Department of Clinical Laboratory, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China.
Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Int J Biol Macromol. 2025 Aug;319(Pt 3):145464. doi: 10.1016/j.ijbiomac.2025.145464. Epub 2025 Jun 23.
The dynamic regulation of RNA N6-methyladenosine (mA) 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.
RNA N6-甲基腺嘌呤（m⁶A）修饰的动态调控对肿瘤的起始、转移和复发起着决定性作用。然而，FTO下游信号通过m⁶A修饰调控乳腺癌发展的潜在机制仍有待进一步研究。在本研究中，我们运用m⁶A甲基化和RNA测序（seq）技术来验证FTO及其下游信号在乳腺癌发展中的作用。在此，我们发现FTO在乳腺癌中异常表达，且对乳腺癌发展至关重要。机制上，FTO通过m⁶A-HNRNPC依赖的方式抑制CYP27B1 mRNA稳定性，随后减少1,25D3合成，并激活STAT3信号通路；p-STAT3进一步激活FTO转录，形成正反馈回路以促进乳腺癌发展。有趣的是，FTO敲低诱导的1,25D3合成增加通过VDR进一步抑制FTO转录，从而减少乳腺癌发展。特别地，FTO的药理抑制作用抑制了肿瘤生长，与化疗联合使用时，能协同消除肿瘤生长并提高体内异种移植肿瘤的化疗敏感性。我们的研究结果强调了FTO/CYP27B1/1,25D3轴在促进乳腺癌发展中的重要作用，并为寻找有效的治疗方法提供了理论依据。
