Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer
Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer
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精氨酸甲基转移酶 PRMT5 通过降低 KLF5 的磷酸化和泛素化来甲基化并稳定 KLF5，从而促进基底样乳腺癌
DOI：
10.1038/s41418-021-00793-0
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发表时间：
2021-05-10
影响因子：
12.4
通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
--
作者：
Wang, Xinye;Qiu, Ting;Chen, Ceshi
Kruppel-like factor5(KLF5)是一种在基底细胞样乳腺癌(BLBC)中高表达的致癌因子，可促进细胞增殖、存活、迁移、干细胞分化和肿瘤生长，但其翻译后修饰尚不清楚。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。在这项研究中，我们发现PRMT5与KLF5相互作用，并在BLBC细胞中以甲基转移酶活性依赖的方式催化精氨酸57(R57)上KLF5的二甲基化。耗尽或药物抑制(使用PJ-68)PRMT5在体内外降低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，进而拮抗Fbw7介导的KLF5泛素化和偶联降解。在功能上，PRMT5至少部分地通过稳定KLF5来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。总而言之，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是治疗BLBC的潜在靶点。
Kruppel-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 GSK3 beta-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.