YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer

作者：Jiang, Dewei; Qiu, Ting; Peng, Junjiang; Li, Siyuan; Tala; Ren, Wenlong; Yang, Chuanyu; Wen, Yi; Chen, Chuan-Huizi; Sun, Jian; Wu, Yingying; Liu, Rong; Zhou, Jun; Wu, Kongming; Liu, Wen; Mao, Xiaoyun^*; Zhou, Zhongmei^*; Chen, Ceshi^*

来源：Cell Death and Differentiation, 2022, 29(6): 1283-1295.

DOI：10.1038/s41418-021-00920-x

• BOX-BINDING PROTEIN-1
• DETERMINATION FACTOR DACH1
• CELL-PROLIFERATION
• RSK ISOFORMS
• EXPRESSION
• YBX1
• GROWTH
• OVEREXPRESSION
• IDENTIFICATION
• CHEMOTHERAPY

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 stabilizing KLF5 mRNA 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) and lymphocyte 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.

• 单位
  云南大学; 1; 华中科技大学; 中国科学院研究生院; 南开大学; 厦门大学; 中国医科大学; 北京大学