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
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KLF5 和 lncRNA KPRT4 之间的前馈回路有助于基底样乳腺癌
DOI：
10.1016/j.canlet.2022.215618
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发表时间：
2022-03-16
期刊：
影响因子：
9.7
通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
--
作者：
Du, Guangshi;Sun, Jian;Chen, Ceshi
基底样乳腺癌（BLBC）是乳腺癌中最具侵袭性的亚型，预后较差。长链非编码RNA（lncRNA）在人类癌症中起关键作用。Kruppel样因子5（KLF 5）是BLBC中的关键致癌转录因子。然而，KLF 5和lncRNA之间相互调节的潜在机制在很大程度上仍然未知。在这里，我们证明了lncRNA KPRT 4在体外和体内促进BLBC细胞增殖。在机制上，KLF 5直接结合KPRT 4的启动子以促进KPRT 4转录。相反，KPRT 4通过在其5 '结构域与YB-1相互作用并在其3 '结构域形成RNA-DNA-DNA三链体结构，将YB-1转录因子募集到KLF 5启动子，导致KLF 5的转录增强并最终建立前馈回路以促进细胞增殖。此外，靶向KPRT 4的基于反义寡核苷酸（阿索）的疗法在体内显著减弱肿瘤生长。临床上，YB-1、KLF 5和KPRT 4在临床乳腺标本中的表达水平呈正相关。总之，我们的数据表明，KPRT 4是BLBC进展的主要分子，KLF 5和KPRT 4之间的前馈回路可能代表BLBC中的潜在治疗靶点。
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. Kruppel-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.