1. Academic Validation
  2. A feedforward circuit between KLF5 and lncRNA KPRT4 contributes to basal-like breast cancer

A feedforward circuit between KLF5 and lncRNA KPRT4 contributes to basal-like breast cancer

  • Cancer Lett. 2022 May 28;534:215618. doi: 10.1016/j.canlet.2022.215618.
Guangshi Du 1 Jian Sun 1 Zhen Li 2 Qian Zhang 2 Wenjing Liu 1 Chuanyu Yang 3 Ping Zhao 2 Xinye Wang 1 Qiyan Yin 4 Yao Luo 4 Jinhuan Song 1 Yi Wen 3 Haixia Wang 5 Chuan-Huizi Chen 3 Guosheng Hu 6 Zhongmei Zhou 3 Xiaoyun Mao 7 Wen Liu 6 Zhenzhen Liu 8 Dewei Jiang 9 Ceshi Chen 10
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, 650201, China; Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, 650204, China.
  • 2 Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, 650201, China.
  • 4 Medical Faculty of Kunming University of Science and Technology, Kunming, 650504, China.
  • 5 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, 650201, China; School of Life Science, University of Science & Technology of China, Hefei, 230027, China.
  • 6 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China.
  • 7 Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
  • 8 Department of Breast Disease, Henan Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China. Electronic address: [email protected].
  • 9 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, 650201, China; Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, 650204, China. Electronic address: [email protected].
  • 10 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, 650201, China. Electronic address: [email protected].
Abstract

Basal-like breast Cancer (BLBC) is the most aggressive subtype of breast Cancer with a poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in human cancers. Krüppel-like Factor 5 (KLF5) is a key oncogenic transcription factor in BLBC. However, the underlying mechanism of mutual regulation between KLF5 and lncRNA remains largely unknown. Here, we demonstrate that lncRNA KPRT4 promotes BLBC cell proliferation in vitro and in vivo. Mechanistically, KLF5 directly binds to the promoter of KPRT4 to promote KPRT4 transcription. Reciprocally, KPRT4 recruits the YB-1 transcription factor to the KLF5 promoter by interacting with YB-1 at its 5' domain and forming an RNA-DNA-DNA triplex structure at its 3' domain, resulting in enhanced transcription of KLF5 and ultimately establishing a feedforward circuit to promote cell proliferation. Moreover, the antisense oligonucleotide (ASO)-based therapy targeting KPRT4 substantially attenuated tumor growth in vivo. Clinically, the expression levels of YB-1, KLF5 and KPRT4 are positively correlated in clinical breast specimens. Together, our data suggest that KPRT4 is a major molecule for BLBC progression and that the feedforward circuit between KLF5 and KPRT4 may represent a potential therapeutic target in BLBC.

Keywords

Antisense oligonucleotide; BLBC; RNA-DNA-DNA triplex Structure; YB-1.

Figures
Products