Zhou Jin, Hepperla Austin, Simon Jeremy M, Kim Kangsan, Hu Qing, Zhang Chuanhai, Dong Lei, Hu Lianxin, Zhang Cheng, Liao Chengheng, Fang Alice, Adachi Yayoi, Fu Haoyong, Wang Tao, Liang Qian, Zhao Fangzhou, Liu Hongyi, Takeda Masashi, Fang Jun, Zhong Hua, Ly Peter, Wang Lu, Kapur Payal, Xu Lin, Jia Liwei, Malladi Srinivas, Brugarolas James, Simon M Celeste, Li Bo, Zhang Qing
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Nat Commun. 2025 Jun 5;16(1):5226. doi: 10.1038/s41467-025-60329-9.
Metastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Here, using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conduct an in vivo genome-wide CRISPR-Cas9 screen and identify HLF as a potent suppressor of lung metastasis. HLF depletion enhances ccRCC cell migration and lung metastasis, whereas HLF overexpression abrogates these effects. In ccRCC patients, HLF expression is reduced at metastatic sites and associates with epigenetic silencing mediated by the SWI/SNF ATPase subunit BRG1. HLF levels negatively correlate with migration potential in collagen. Mechanistically, HLF regulates LPXN expression, modulating the integration of collagen's mechanical cues with the actin cytoskeleton through Paxillin, thereby suppressing cancer cell migration and lung metastasis. Overexpression of HLF or pharmacological inhibition of BRG1 reduces cell invasion across multiple cancer types. Our findings suggest that targeting the BRG1-HLF axis offers a promising therapeutic strategy for combating metastatic cancers.
转移是癌症相关死亡的主要原因，但其潜在机制仍不清楚。在这里，我们使用透明细胞肾细胞癌（ccRCC）——一种经常发生肺转移的肿瘤类型，进行了一项全基因组体内CRISPR-Cas9筛选，并确定HLF是肺转移的有效抑制因子。HLF缺失增强了ccRCC细胞的迁移和肺转移，而HLF过表达则消除了这些作用。在ccRCC患者中，HLF在转移部位的表达降低，并与由SWI/SNF ATP酶亚基BRG1介导的表观遗传沉默相关。HLF水平与胶原蛋白中的迁移潜能呈负相关。从机制上讲，HLF调节LPXN的表达，通过桩蛋白调节胶原蛋白的机械信号与肌动蛋白细胞骨架的整合，从而抑制癌细胞的迁移和肺转移。HLF的过表达或BRG1的药理学抑制可减少多种癌症类型的细胞侵袭。我们的研究结果表明，靶向BRG1-HLF轴为对抗转移性癌症提供了一种有前景的治疗策略。
