Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, Yunnan, China.
Cell Death Differ. 2021 Oct;28(10):2931-2945. doi: 10.1038/s41418-021-00793-0. Epub 2021 May 10.
Krüppel-like factor 5 (KLF5) is an oncogenic factor that is highly expressed in basal-like breast cancer (BLBC) and promotes cell proliferation, survival, migration, stemness, and tumor growth; however, its posttranslational modifications are poorly defined. Protein arginine methyltransferase 5 (PRMT5) is also an oncogene implicated in various carcinomas, including breast cancer. In this study, we found that PRMT5 interacts with KLF5 and catalyzes the di-methylation of KLF5 at Arginine 57 (R57) in a methyltransferase activity-dependent manner in BLBC cells. Depletion or pharmaceutical inhibition (using PJ-68) of PRMT5 decreased the expression of KLF5 and its downstream target genes in vitro and in vivo. PRMT5-induced KLF5R57me2 antagonizes GSK3β-mediated KLF5 phosphorylation and subsequently Fbw7-mediated KLF5 ubiquitination and coupled degradation. Functionally, PRMT5 promotes breast cancer stem cell maintenance and proliferation, at least partially, by stabilizing KLF5. PRMT5 and KLF5 protein levels were positively correlated in clinical BLBCs. Taken together, PRMT5 methylates KLF5 to prevent its phosphorylation, ubiquitination, and degradation, and thus promotes breast cancer stem cell maintenance and proliferation. These findings suggest that PRMT5 is a potential therapeutic target for BLBC.
Krüppel 样因子 5（KLF5）是一种致癌因子，在基底样乳腺癌（BLBC）中高度表达，促进细胞增殖、存活、迁移、干性和肿瘤生长；然而，其翻译后修饰仍知之甚少。蛋白精氨酸甲基转移酶 5（PRMT5）也是一种癌基因，与多种癌症有关，包括乳腺癌。在本研究中，我们发现 PRMT5 与 KLF5 相互作用，并以依赖于甲基转移酶活性的方式在 BLBC 细胞中催化 KLF5 在精氨酸 57（R57）处的二甲基化。PRMT5 的耗竭或药物抑制（使用 PJ-68）减少了体外和体内 KLF5 及其下游靶基因的表达。PRMT5 诱导的 KLF5R57me2 拮抗 GSK3β 介导的 KLF5 磷酸化，随后 Fbw7 介导的 KLF5 泛素化和偶联降解。功能上，PRMT5 通过稳定 KLF5 至少部分促进乳腺癌干细胞的维持和增殖。PRMT5 和 KLF5 蛋白水平在临床 BLBC 中呈正相关。综上所述，PRMT5 甲基化 KLF5 以防止其磷酸化、泛素化和降解，从而促进乳腺癌干细胞的维持和增殖。这些发现表明 PRMT5 是 BLBC 的一个潜在治疗靶点。
