YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer PMID: 35022570

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
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. [email protected].
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. [email protected].
13. Kunming College of Lifesciences, University of Chinese Academy Sciences, Kunming, China. [email protected].
14. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. [email protected].
# 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.