Ai-lncRNA EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions in human cancer

• Published in: Molecular cancer Vol. 18; no. 1; pp. 89 - 18
• Main Authors: Xu, Shouping, Wang, Peiyuan, Zhang, Jian, Wu, Hao, Sui, Shiyao, Zhang, Jinfeng, Wang, Qin, Qiao, Kun, Yang, Weiwei, Xu, Hongbiao, Pang, Da
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.04.2019; BioMed Central; BMC
• Subjects: Adult; Aged; Ai-lncRNA; Alternative splicing; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Antisense RNA; Autophagosomes - metabolism; Autophagy; Autophagy - drug effects; Autophagy - genetics; Binding sites; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer; Cancer patients; Cancer therapies; Cell Line, Tumor; Chemotherapy; Chromatin; Cytotoxicity; Double-stranded RNA; Drug Resistance, Neoplasm - genetics; EGOT; Experiments; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Genomes; Health aspects; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism; Humans; Hypoxia; Immunoprecipitation; Inositol 1,4,5-Trisphosphate Receptors - antagonists & inhibitors; Inositol 1,4,5-Trisphosphate Receptors - genetics; Inositol 1,4,5-Trisphosphate Receptors - metabolism; ITPR1; Medical prognosis; Metabolism; Mice; Mice, Nude; Middle Aged; Novels; Nucleotides; Paclitaxel; Paclitaxel - pharmacology; Phagocytosis; Protein Binding; Protein interaction; Ribonucleic acid; RNA; RNA, Double-Stranded - genetics; RNA, Double-Stranded - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA-protein interactions; Signal Transduction; Survival Analysis; Toxicity; Transcription; Transcription (Genetics); Transcriptome; Tumors; Up-regulation; Xenograft Model Antitumor Assays; United States > US; China; ITPR1; Ai-lncRNA; Autophagy; EGOT; Paclitaxel; Cancer
• DOI: 10.1186/s12943-019-1017-z
• ISSN: 1476-4598

The biology function of antisense intronic long noncoding RNA (Ai-lncRNA) is still unknown. Meanwhile, cancer patients with paclitaxel resistance have limited therapeutic options in the clinic. However, the potential involvement of Ai-lncRNA in paclitaxel sensitivity remains unclear in human cancer. Whole transcriptome sequencing of 33 breast specimens was performed to identify Ai-lncRNA EGOT. Next, the role of EGOT in regulation of paclitaxel sensitivity was investigated. Moreover, the mechanism of EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions was investigated in detail. Furthermore, upstream transcriptional regulation of EGOT expression was also investigated by co-immunoprecipitation and chromatin immunoprecipitation. Finally, clinical breast specimens in our cohort, TCGA and ICGC were applied to validate the role of EGOT in enhancing of paclitaxel sensitivity. EGOT enhances autophagosome accumulation via the up-regulation of ITPR1 expression, thereby sensitizing cells to paclitaxel toxicity. Mechanistically, on one hand, EGOT upregulates ITPR1 levels via formation of a pre-ITPR1/EGOT dsRNA that induces pre-ITPR1 accumulation to increase ITPR1 protein expression in cis. On the other hand, EGOT recruits hnRNPH1 to enhance the alternative splicing of pre-ITPR1 in trans via two binding motifs in EGOT segment 2 (324-645 nucleotides) in exon 1. Moreover, EGOT is transcriptionally regulated by stress conditions. Finally, EGOT expression enhances paclitaxel sensitivity via assessment of cancer specimens. These findings broaden comprehensive understanding of the biology function of Ai-lncRNAs. Proper regulation of EGOT may be a novel synergistic strategy for enhancing paclitaxel sensitivity in cancer therapy.