Department of Pathology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
Department of Cancer Biology and Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.
Mol Cancer Res. 2018 Mar;16(3):439-452. doi: 10.1158/1541-7786.MCR-17-0364. Epub 2018 Jan 12.
The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here, it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with proglycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells toward a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNA sequencing (RNAseq) confirms deregulation of metabolic genes downstream of Oct1. BRCA1 mediates Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenograft assays. In primary breast cancer clinical specimens, Oct1 protein levels correlate positively with tumor aggressiveness and inversely with BRCA1. These results identify BRCA1 as an Oct1 ubiquitin ligase that catalyzes Oct1 degradation to promote oxidative metabolism and restrict tumorigenicity. .
肿瘤抑制因子 BRCA1 调节 DNA 损伤反应（DDR）和其他尚未完全定义的过程。在这些过程中，BRCA1 与 BARD1 异二聚化，通过其 N 端 E3 连接酶活性泛素化靶标。在这里，研究表明 BRCA1 通过降解转录因子 Oct1（POU2F1）来促进氧化代谢，Oct1 具有促进糖酵解和致瘤作用。BRCA1 E3 泛素连接酶突变使细胞偏向糖酵解代谢特征，同时提高 Oct1 蛋白水平。CRISPR 介导的 Oct1 缺失使糖酵解表型恢复正常。RNA 测序（RNAseq）证实代谢基因下游的代谢基因失调。BRCA1 介导 Oct1 的泛素化和降解，而两个泛素化的 Oct1 赖氨酸的突变使该蛋白免受 BRCA1 介导的不稳定。在 MCF-7 乳腺癌细胞中删除 Oct1 不会扰乱标准培养物中的生长，但会抑制软琼脂和异种移植测定中的生长。在原发性乳腺癌临床标本中，Oct1 蛋白水平与肿瘤侵袭性呈正相关，与 BRCA1 呈负相关。这些结果表明 BRCA1 是 Oct1 的泛素连接酶，可催化 Oct1 的降解，以促进氧化代谢并限制致瘤性。
