Xu Lele, Chen Yuting, Wu Tao, Fan Jiaqi, Hu Yuying, Gao Xuefeng, Wang Yuliang, Chen Tao, Zhao Xueting, Zeng Min, Wang Fei, Zheng Qingyou, Pei Xiaojuan, Wu Dinglan
Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
The Third School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong, China.
iScience. 2024 Jul 14;27(8):110505. doi: 10.1016/j.isci.2024.110505. eCollection 2024 Aug 16.
Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a promising novel treatment for castration-resistant prostate cancer (CRPC) with encouraging results. However, the combination targets in CRPC remain largely unexplored. N6-methyladenosine (mA) has been shown to play a crucial role in cancer progression and DNA damage response. Here, we observed a higher overall level of mA and a downregulation of Fat mass and obesity-associated protein (FTO), which correlated with unfavorable clinicopathological parameters in prostate cancer (PCa). Functionally, reduced FTO promotes PCa growth, while overexpression of FTO has the opposite effect. Mechanistically, FOXO3a was identified as the downstream target of FTO in PCa. FTO downregulates the expression of FOXO3a in an mA-dependent manner, leading to the degradation of its mRNA. Importantly, DNA damage can degrade FTO through the ubiquitination pathway. Finally, we found that overexpression of FTO can enhance the effect of PARPi on PCa. Therefore, our findings may provide insight into novel therapeutic approaches for CRPC.
聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）是去势抵抗性前列腺癌（CRPC）一种很有前景的新型治疗方法，已取得了令人鼓舞的结果。然而，CRPC中的联合靶点在很大程度上仍未得到探索。N6-甲基腺苷（mA）已被证明在癌症进展和DNA损伤反应中起关键作用。在此，我们观察到前列腺癌（PCa）中mA的总体水平较高，且脂肪量和肥胖相关蛋白（FTO）下调，这与不良的临床病理参数相关。在功能上，FTO减少促进PCa生长，而FTO过表达则有相反的效果。在机制上，FOXO3a被确定为PCa中FTO的下游靶点。FTO以mA依赖的方式下调FOXO3a的表达，导致其mRNA降解。重要的是，DNA损伤可通过泛素化途径降解FTO。最后，我们发现FTO过表达可增强PARPi对PCa的作用。因此，我们的研究结果可能为CRPC的新型治疗方法提供见解。
