Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA.
Southeast Center for Integrated Metabolomics, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA.
Nat Commun. 2023 Apr 12;14(1):1927. doi: 10.1038/s41467-023-37501-0.
Cancer cells exhibit elevated lipid synthesis. In breast and other cancer types, genes involved in lipid production are highly upregulated, but the mechanisms that control their expression remain poorly understood. Using integrated transcriptomic, lipidomic, and molecular studies, here we report that DAXX is a regulator of oncogenic lipogenesis. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipogenesis, and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and DAXX mutants unable to bind SREBP1/2 have weakened activity in promoting lipogenesis and tumor growth. Remarkably, a DAXX mutant deficient of SUMO-binding fails to activate SREBP1/2 and lipogenesis due to impaired SREBP binding and chromatin recruitment and is defective of stimulating tumorigenesis. Hence, DAXX's SUMO-binding activity is critical to oncogenic lipogenesis. Notably, a peptide corresponding to DAXX's C-terminal SUMO-interacting motif (SIM2) is cell-membrane permeable, disrupts the DAXX-SREBP1/2 interactions, and inhibits lipogenesis and tumor growth. These results establish DAXX as a regulator of lipogenesis and a potential therapeutic target for cancer therapy.
癌细胞表现出升高的脂质合成。在乳腺和其他癌症类型中，涉及脂质生成的基因高度上调，但控制其表达的机制仍知之甚少。通过整合转录组学、脂质组学和分子研究，我们在这里报告 DAXX 是一种致癌脂质生成的调节剂。DAXX 耗竭会减弱，而过表达则会增强，脂质生成基因的表达、脂质生成和肿瘤生长。从机制上讲，DAXX 与 SREBP1 和 SREBP2 相互作用并激活 SREBP 介导的转录。DAXX 通过 SREBPs 与脂质生成基因启动子结合。DAXX-SREBP 相互作用对脂质生成的关键作用强调了这一点，SREBP2 敲低可减弱过表达 DAXX 的细胞中的肿瘤生长，并且无法与 SREBP1/2 结合的 DAXX 突变体在促进脂质生成和肿瘤生长方面的活性减弱。值得注意的是，由于 SREBP 结合和染色质募集受损，缺乏 SUMO 结合的 DAXX 突变体无法激活 SREBP1/2 和脂质生成，并且无法刺激肿瘤发生。因此，DAXX 的 SUMO 结合活性对于致癌脂质生成至关重要。值得注意的是，对应于 DAXX 的 C 末端 SUMO 相互作用基序（SIM2）的肽是细胞膜可渗透的，破坏了 DAXX-SREBP1/2 相互作用，并抑制了脂质生成和肿瘤生长。这些结果确立了 DAXX 作为脂质生成调节剂和癌症治疗的潜在治疗靶点。
