美国圣犹达儿童研究医院Charles W. M. Roberts和美国丹娜-法伯癌症研究所Eric S. Fischer共同合作，近期取得重要工作进展。他们研究提出，靶向DCAF5可通过稳定SWI/SNF复合物来抑制SMARCB1突变型癌症。相关研究成果2024年3月27日在线发表于《自然》杂志上。

据介绍，尽管癌基因可能被小分子抑制，但肿瘤抑制因子的丢失在癌症中更为常见，由于肿瘤抑制蛋白损失，将无法作为治疗靶点。例如SMARCB1突变癌症，这是由SWI/SNF（也称为BAF）染色质重塑复合物的亚基失活驱动的高致死性恶性肿瘤。

为了对SMARCB1突变的后果产生机制性见解，研究人员将14个SMARCB1突变细胞系用于全基因组CRISPR筛查。研究人员报道了很少研究的基因DDB1–CUL4相关因子5（DCAF5）是SMARCB1突变癌症生存所必需的。研究人员发现DCAF5对SWI/SNF复合物具有质量控制功能，并在缺乏SMARCB1的情况下促进不完全组装的SWI/SNF配合物的降解。

在DCAF5缺失后，SMARCB1缺乏的SWI/SNF复合物重新积累，与靶基因座结合，并将SWI/SNF介导的基因表达恢复到足以逆转癌症状态的水平，包括在体内。因此，癌症不是由SMARCB1功能本身的丧失引起的，而是由DCAF5介导的SWI/SNF复合物的降解引起的。

总之，这些数据表明，泛素介导的质量控制因子的治疗靶向可以有效逆转，由肿瘤抑制复合物破坏而驱动的一些癌症的恶性状态。

附：英文原文

Title: Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF

Author: Radko-Juettner, Sandi, Yue, Hong, Myers, Jacquelyn A., Carter, Raymond D., Robertson, Alexis N., Mittal, Priya, Zhu, Zhexin, Hansen, Baranda S., Donovan, Katherine A., Hunkeler, Moritz, Rosikiewicz, Wojciech, Wu, Zhiping, McReynolds, Meghan G., Roy Burman, Shourya S., Schmoker, Anna M., Mageed, Nada, Brown, Scott A., Mobley, Robert J., Partridge, Janet F., Stewart, Elizabeth A., Pruett-Miller, Shondra M., Nabet, Behnam, Peng, Junmin, Gray, Nathanael S., Fischer, Eric S., Roberts, Charles W. M.

Issue&Volume: 2024-03-27

Abstract: Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1,2,3. We report that the little-studied gene DDB1–CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

DOI: 10.1038/s41586-024-07250-1

Source: https://www.nature.com/articles/s41586-024-07250-1