Long Noncoding RNA TINCR-Mediated Regulation of Acetyl-CoA Metabolism Promotes Nasopharyngeal Carcinoma Progression and Chemoresistance

Zi-Qi Zheng,Yue Chen,Guan-Qun Zhou,Xu Liu,Li Lin,Na Liu,Feng Li,Jia-Li Guan,Jun Ma,Jia Kou,Ying Sun,Xiaoxi He ,Shihe Xu ,Ruiqi Liu ,Lulu Zhang ,Fo-Ping Chen ,Ying‐Qin Li ,Jiawei Lv ,Zhixuan Li ,Junyan Li

doi:10.1158/0008-5472.can-19-3626

Abstract

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)-MAPK-MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR-ACLY-PADI1-MAPK-MMP2/9 axis as a potential therapeutic target in NPC. SIGNIFICANCE: TINCR-mediated regulation of a PADI1-MAPK-MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.

Highlights

Nasopharyngeal carcinoma (NPC), one of the most common cancers originating in the nasopharynx, is prevalent in Southeastern Asia and North Africa [1]
We found that TINCR expression was much higher in 11 NPC cell lines than in NP69 and N2Tert cells (Fig. 1C)
On the basis of The Cancer Genome Atlas (TCGA) database, we found that TINCR was upregulated in six other cancer types (Supplementary Fig. S1)

Summary

Introduction

Nasopharyngeal carcinoma (NPC), one of the most common cancers originating in the nasopharynx, is prevalent in Southeastern Asia and North Africa [1]. With the development of intensity-modulated radiotherapy and cisplatin-based concurrent chemotherapy, locoregional control of NPC has improved greatly [2]. Dominates the treatment failure of this disease. We reconfirmed the effectiveness of cisplatin-based induction chemotherapy in controlling distant failure and improving survival [3]; patients with stable disease after induction chemotherapy, indicating resistance to this cisplatin-based therapy, Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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Conclusion