1. Academic Validation
  2. 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

  • Cell Death Differ. 2022 Jun;29(6):1283-1295. doi: 10.1038/s41418-021-00920-x.
Dewei Jiang  # 1 2 Ting Qiu  # 1 2 Junjiang Peng  # 1 Siyuan Li  # 1 Tala 3 Wenlong Ren 1 4 Chuanyu Yang 1 Yi Wen 1 Chuan-Huizi Chen 5 Jian Sun 1 2 Yingying Wu 6 Rong Liu 7 Jun Zhou 3 Kongming Wu 8 Wen Liu 9 Xiaoyun Mao 10 Zhongmei Zhou 11 Ceshi Chen 12 13 14
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 2 Kunming College of Lifesciences, University of Chinese Academy Sciences, Kunming, China.
  • 3 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
  • 4 College of Life Sciences, China University of Science and Technology, Hefei, Anhui, China.
  • 5 School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, China.
  • 6 The First Affiliated Hospital, Kunming Medical University, Kunming, China.
  • 7 The First Affiliated Hospital, Peking University, Beijing, China.
  • 8 Department of Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
  • 9 School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, China.
  • 10 Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China. xymao@cmu.edu.cn.
  • 11 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. zhouzm@mail.kiz.ac.cn.
  • 12 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. chenc@mail.kiz.ac.cn.
  • 13 Kunming College of Lifesciences, University of Chinese Academy Sciences, Kunming, China. chenc@mail.kiz.ac.cn.
  • 14 KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. chenc@mail.kiz.ac.cn.
  • # Contributed equally.
Abstract

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.

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