LncRNA CISAL Inhibits BRCA1 Transcription by Forming a Tertiary Structure at Its Promoter.

Qunxing Li,Sheng Sun,Xinyu Lin,Xinyuan Lei,Sigeng Lin,Shuhua Xie ,Yu Peng,Zhanpeng Ou,Bowen Li,Zhaohui Yang,Faya Liang,Filippos Kontos,Tian Tian,Jinsong Li,Liping Xiao,Bakhos A. Tannous,De‐Chen Lin ,Binghui Zeng,Soldano Ferrone,St Fan ,Weixiong Chen,Hanqing Zhang,Yin Zhang,Xiaobin Lv,Shunrong Li,Yi Ruan,Lizao Zhang,Guokai Pan,Xiaofeng Lin,Zhaoyu Lin,Mo Liu

doi:10.1016/j.isci.2020.100835

Abstract

SummaryCisplatin-based neoadjuvant chemotherapy has been shown to improve survival in patients with squamous cell carcinoma (SCC), but clinical biomarkers to predict chemosensitivity remain elusive. Here, we show the long noncoding RNA (lncRNA) LINC01011, which we termed cisplatin-sensitivity-associated lncRNA (CISAL), controls mitochondrial fission and cisplatin sensitivity by inhibiting BRCA1 transcription in tongue SCC (TSCC) models. Mechanistically, we found CISAL directly binds the BRCA1 promoter and forms an RNA-DNA triplex structure, sequestering BRCA1 transcription factor-GABPA away from the downstream regulatory binding region. Importantly, the clinical relevance of these findings is suggested by the significant association of CISAL and BRCA1 expression levels in TSCC tumors with neoadjuvant chemosensitivity and overall survival. We propose a new model where lncRNAs are tethered at gene promoter by RNA-DNA triplex formation, spatially sequestering transcription factors away from DNA-binding sites. Our study uncovers the potential of CISAL-BRCA1 signaling as a potential target to predict or improve chemosensitivity.

Highlights

Around 70% of the human genome is transcribed to RNA, whereas only 2% consists of protein-coding genes (Ulitsky and Bartel, 2013)
Differential Expression of long noncoding RNA (lncRNA) Induced by Cisplatin in tongue squamous cell carcinoma (TSCC) Cells and Tumor Tissues Recent studies have demonstrated that lncRNAs play pivotal roles in regulating the biological properties of cancer (Peng et al, 2017)
We showed that mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma (TSCC) (Fan et al, 2015a, 2015b)

Summary

Introduction

Around 70% of the human genome is transcribed to RNA, whereas only 2% consists of protein-coding genes (Ulitsky and Bartel, 2013). LncRNAs can serve as scaffolds or guides to regulate protein-protein or protein-DNA interactions as decoys to bind proteins or microRNAs (miRNAs) and as enhancers to influence gene transcription when transcribed from enhancer regions (enhancer RNA) or their neighboring loci (ncRNA activator) (Hu et al, 2014). These lncRNAs have emerged as key regulators of important biological processes implicated in cell proliferation (Bian et al, 2018), differentiation (Russell et al, 2015), migration (Wang et al, 2017), immune response (Heward and Lindsay, 2014), and apoptosis in various cancer types, acting as tumor suppressors or oncogenes (Liu et al, 2018; Xing et al, 2018).

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