Guo Jiacheng, Li Ni, Liu Qiuli, Hao Zongyao, Zhu Guanghui, Wang Xuege, Wang Hanling, Pan Qiang, Xu Beitao, Han Ying, Zhang Guoying, Lian Yannan, Zhang Wei, Gu Yongqiang, Lin Naiheng, Zeng Xin, Jin Zige, Lan Weihua, Jiang Jun, Gao Dong, Dong Liang, Yuan Huairui, Liang Chaozhao, Qin Jun
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Jinfeng Laboratory, Chongqing 401329, China.
Cancer Cell. 2025 Jul 14;43(7):1261-1278.e10. doi: 10.1016/j.ccell.2025.04.002. Epub 2025 Apr 24.
Double-negative prostate cancer (DNPC), characterized by an androgen receptor (AR)- and neuroendocrine-null phenotype, frequently emerges following androgen deprivation therapy (ADT). However, our understanding of the origins and regulatory mechanisms of DNPC remains limited. Here, we discover that tumors with KMT2C mutation or loss are highly susceptible to transitioning into DNPC following ADT. We clarify that DNPC primarily stems from luminal cell transdifferentiation rather than basal cell transformation. Antiandrogen treatment induces KMT2C binding at enhancers of a subset of AR-regulated genes, preserving the adenocarcinoma lineage. KMT2C maintains ASPP2 expression via enhancer-promoter communication post-AR inhibition, while its inactivation reduces ASPP2, triggering ΔNp63-dependent transdifferentiation. This DNPC transition maintains fatty acid (FA) synthesis through ΔNp63-mediated SREBP1c transactivation, fueling DNPC growth via HRAS palmitoylation and MAPK signaling activation. These findings highlight KMT2C as an epigenetic checkpoint against DNPC development and suggest the therapeutic potential of targeting fatty acid synthesis.
双阴性前列腺癌（DNPC）以雄激素受体（AR）和神经内分泌缺失表型为特征，常在雄激素剥夺治疗（ADT）后出现。然而，我们对DNPC的起源和调控机制的了解仍然有限。在这里，我们发现具有KMT2C突变或缺失的肿瘤在ADT后极易转变为DNPC。我们阐明，DNPC主要源于管腔细胞转分化而非基底细胞转化。抗雄激素治疗诱导KMT2C在AR调控基因子集的增强子处结合，维持腺癌谱系。AR抑制后，KMT2C通过增强子-启动子通讯维持ASPP2表达，而其失活会降低ASPP2，触发ΔNp63依赖的转分化。这种DNPC转变通过ΔNp63介导的SREBP1c反式激活维持脂肪酸（FA）合成，通过HRAS棕榈酰化和MAPK信号激活促进DNPC生长。这些发现突出了KMT2C作为对抗DNPC发展的表观遗传检查点，并提示了靶向脂肪酸合成的治疗潜力。
