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

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.

• Authors: Dewei Jiang, Ting Qiu, Junjiang Peng, Siyuan Li, Tala, Wenlong Ren, Chuanyu Yang, Yi Wen, Chuan-Huizi Chen, Jian Sun, Yingying Wu, Rong Liu, Jun Zhou, Kongming Wu, Wen Liu, Xiaoyun Mao, Zhongmei Zhou, Ceshi Chen
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 29 Issue 6 Pg. 1283-1295 (06 2022) ISSN: 1476-5403 [Electronic] England
• PMID: 35022570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

Chemical References

• DACH1 protein, human
• Eye Proteins
• KLF5 protein, human
• Kruppel-Like Transcription Factors
• RNA, Messenger
• Transcription Factors
• Y-Box-Binding Protein 1
• YBX1 protein, human
• RNA
• 5-Methylcytosine

Topics

• 5-Methylcytosine (metabolism)
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Eye Proteins (genetics, metabolism)
• Female
• Humans
• Kruppel-Like Transcription Factors (genetics, metabolism)
• RNA (metabolism)
• RNA, Messenger (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Y-Box-Binding Protein 1 (genetics, metabolism)