YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer
YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer
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YB-1 是基底样乳腺癌中 KLF5 转录因子的正调节因子。
DOI：
10.1038/s41418-021-00920-x
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发表时间：
2022-01-13
影响因子：
12.4
通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
--
作者：
Jiang, Dewei;Qiu, Ting;Chen, Ceshi
Y-box结合蛋白1（YB-1）是一种已知的癌基因，在多种癌症中高度表达，包括基底样乳腺癌（BLBC）。除了作为转录因子的作用之外，YB-1被新定义为涉及RNA 5-甲基胞嘧啶的表观遗传调节因子。然而，其特定的靶点和促癌功能的定义很差。在这里，基于临床数据库，我们证明了乳腺癌患者中Kruppel样因子5（KLF 5）和YB-1的表达呈正相关，但与腊肠犬同源物1（DACH 1）呈负相关。YB-1增强KLF 5表达的机制不仅是通过转录激活（DACH 1可抑制转录激活），而且通过稳定KLF 5 mRNA以RNA 5-甲基胞嘧啶修饰依赖的方式。此外，核糖体S6激酶2（RSK 2）介导的YB-1在Ser 102处的磷酸化促进YB-1/KLF 5转录复合物的形成，其共调节BLBC特异性基因角蛋白16（KRT 16）和淋巴细胞抗原6家族成员D（Ly 6D）的表达，从而促进癌细胞增殖。RSK抑制剂LJH 685通过干扰YB-1-KLF 5轴抑制BLBC细胞体内成瘤。我们的数据表明，YB-1积极调节KLF 5在多个水平，以促进BLBC的进展。新的RSK 2-YB-1-KLF 5-KRT 16/Ly 6D轴为BLBC提供了候选的诊断标志物和治疗靶点。
Y-box binding protein 1 (YB-1) is a well-known oncogene highly expressed in various cancers, including basal-like breast cancer (BLBC). Beyond its role as a transcription factor, YB-1 is newly defined as an epigenetic regulator involving RNA 5-methylcytosine. However, its specific targets and pro-cancer functions are poorly defined. Here, based on clinical database, we demonstrate a positive correlation between Kruppel-like factor 5 (KLF5) and YB-1 expression in breast cancer patients, but a negative correlation with that of Dachshund homolog 1 (DACH1). Mechanistically, YB-1 enhances KLF5 expression not only through transcriptional activation that can be inhibited by DACH1, but also by stabilizingKLF5mRNA in a RNA 5-methylcytosine modification-dependent manner. Additionally, ribosomal S6 kinase 2 (RSK2) mediated YB-1 phosphorylation at Ser102 promotes YB-1/KLF5 transcriptional complex formation, which co-regulates the expression of BLBC specific genes,Keratin 16 (KRT16)andlymphocyte antigen 6 family member D (Ly6D), to promote cancer cell proliferation. The RSK inhibitor, LJH685, suppressed BLBC cell tumourigenesis in vivo by disturbing YB-1-KLF5 axis. Our data suggest that YB-1 positively regulates KLF5 at multiple levels to promote BLBC progression. The novel RSK2-YB-1-KLF5-KRT16/Ly6D axis provides candidate diagnostic markers and therapeutic targets for BLBC.