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.
Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China.
Cancer Lett. 2022 May 28;534:215618. doi: 10.1016/j.canlet.2022.215618. Epub 2022 Mar 6.
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.
基底样乳腺癌（BLBC）是乳腺癌中最具侵袭性的亚型，预后不良。长链非编码 RNA（lncRNA）在人类癌症中发挥着关键作用。Krüppel 样因子 5（KLF5）是 BLBC 中的关键致癌转录因子。然而，KLF5 和 lncRNA 之间相互调节的潜在机制在很大程度上尚不清楚。在这里，我们证明 lncRNA KPRT4 促进 BLBC 细胞在体外和体内的增殖。在机制上，KLF5 直接结合 KPRT4 启动子以促进 KPRT4 转录。反过来，KPRT4 通过与其 5' 结构域相互作用将 YB-1 转录因子募集到 KLF5 启动子，并在其 3' 结构域形成 RNA-DNA-DNA 三链结构，从而增强 KLF5 的转录，最终建立一个正反馈回路以促进细胞增殖。此外，针对 KPRT4 的反义寡核苷酸（ASO）疗法在体内显著减弱了肿瘤生长。临床上，YB-1、KLF5 和 KPRT4 的表达水平在临床乳腺标本中呈正相关。总之，我们的数据表明 KPRT4 是 BLBC 进展的主要分子，而 KLF5 和 KPRT4 之间的正反馈回路可能代表 BLBC 中的一个潜在治疗靶点。
