Ren Yuliang, Chen Junjie, Zhan Xiangrong, Sheng Songran, Zhong Yifan, Gu Manxiang, Liu Xuewen, Zhang Liang, Bao Lei, Si Yuan, Liu Ying
Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China.
General Hospital of Yangquan Coal Industry Group, Yangquan, Shanxi, China.
Oncogene. 2025 Jul 25. doi: 10.1038/s41388-025-03498-7.
Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC), yet the underlying regulatory mechanisms remain incompletely understood. Here, we identified G protein pathway suppressor 2 (GPS2) as a pivotal oncogenic driver that orchestrates lipid metabolic reprogramming to fuel CRC progression. Clinically, GPS2 is overexpressed in CRC and is correlated with aggressive phenotypes. Functionally, GPS2 depletion inhibits tumor growth in vitro and in vivo, whereas its overexpression accelerates malignancy. Mechanistically, GPS2 dual-regulates lipid metabolism by facilitating the nuclear translocation of sterol regulatory element-binding protein 1 (SREBP1) to activate lipid synthesis and by increasing peroxisome proliferator-activated receptor α (PPARα) transcription to promote fatty acid oxidation. Crucially, we revealed that GPS2 undergoes liquid-liquid phase separation (LLPS) in CRC cells, where it forms biomolecular condensates that promote oncogenic signaling. Through its coiled-coil domain, phase-separated GPS2 directly interacts with the C-terminal kinase domain of large tumor suppressor 1 (LATS1), a core kinase of the Hippo pathway, inducing LLPS of LATS1 and suppressing its activity. This inactivation releases YAP, which in turn amplifies SREBP1/PPARα-driven lipid metabolism. Rescue experiments confirmed that YAP reconstitution restores SREBP1 nuclear translocation and PPARα transcription upon GPS2 loss, establishing the LATS1-YAP axis as the central effector of GPS2-mediated lipid metabolic programming. Our study delineates a novel phase separation-dependent mechanism whereby GPS2 spatially reorganizes LATS1-YAP signaling to reprogram lipid metabolism and promote CRC progression, suggesting potential therapeutic targets for metabolic intervention in CRC.
异常脂质代谢是结直肠癌（CRC）的一个标志，但其潜在的调控机制仍未完全明确。在此，我们确定G蛋白信号通路抑制因子2（GPS2）是一个关键的致癌驱动因子，它协调脂质代谢重编程以推动CRC进展。在临床上，GPS2在CRC中过表达，并与侵袭性表型相关。在功能上，GPS2缺失在体外和体内均抑制肿瘤生长，而其过表达则加速恶性肿瘤进程。机制上，GPS2通过促进固醇调节元件结合蛋白1（SREBP1）的核转位以激活脂质合成，以及通过增加过氧化物酶体增殖物激活受体α（PPARα）转录以促进脂肪酸氧化，对脂质代谢进行双重调节。至关重要的是，我们发现GPS2在CRC细胞中发生液-液相分离（LLPS），在那里它形成促进致癌信号传导的生物分子凝聚物。通过其卷曲螺旋结构域，相分离的GPS2直接与大肿瘤抑制因子1（LATS1）的C末端激酶结构域相互作用，LATS1是Hippo通路的核心激酶，诱导LATS1发生LLPS并抑制其活性。这种失活释放YAP，进而放大SREBP1/PPARα驱动的脂质代谢。挽救实验证实，YAP的重建可在GPS2缺失时恢复SREBP1核转位和PPARα转录，确立LATS1-YAP轴为GPS2介导的脂质代谢编程的中心效应器。我们的研究描绘了一种新的相分离依赖性机制，即GPS2在空间上重组LATS1-YAP信号传导以重编程脂质代谢并促进CRC进展，提示CRC代谢干预的潜在治疗靶点。
