NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay

• Published in: Oncogene 2021-07, Vol.40 (30), p.4919-4929
• Main Authors: Zhao, Lin, Jiang, Longyang, Zhang, Ming, Zhang, Qiang, Guan, Qiutong, Li, Yalun, He, Miao, Zhang, Jingdong, Wei, Minjie
• Format: Article
• Language: English
• Subjects: 13/109; 13/51; 13/89; 3' Untranslated Regions; 38/32; 631/67; 631/80; 64/60; Alu Elements; Apoptosis; Binding Sites; Breast cancer; Cell Biology; Cell Line, Tumor; Colorectal cancer; Colorectal carcinoma; Cytoskeletal Proteins - metabolism; DNA microarrays; Elongin - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Human Genetics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunohistochemistry; Internal Medicine; Medicine; Medicine & Public Health; Metastases; Metastasis; miRNA; Molecular modelling; mRNA stability; mRNA turnover; Neoplasm Metastasis; Neoplasm Staging; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; NF-kappa B - metabolism; NF-κB protein; Non-coding RNA; Oncology; Ovarian cancer; RNA Interference; RNA Stability; RNA, Long Noncoding - genetics; RNA-Binding Proteins - metabolism; Signal Transduction; Transcription elongation factor b
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01900-8

Previous study demonstrated that most long non-coding RNAs (lncRNAs) function as competing endogenous RNAs or molecular sponges to negatively modulate miRNA and regulate tumor development. However, the molecular mechanisms of lncRNAs in cancer are not fully understood. Our study describes the role of the lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) in cancer metastasis by mechanisms related to Staufen1 (STAU1)-mediated mRNA decay (SMD). Briefly, we found that, high SPRY4-IT1 expression was associated with aggressiveness and poor outcome in human colorectal, breast and ovarian cancer tissues. In addition, functional assays revealed that SPRY4-IT1 significantly promoted colorectal, breast and ovarian cancer metastasis in vitro and in vivo. Mechanistically, microarray analyses identified several differentially-expressed genes upon SPRY4-IT1 overexpression in HCT 116 colorectal cancer cells. Among them, the 3′-UTR of transcription elongation factor B subunit 1 ( TCEB1 ) mRNA can base-pair with the Alu element in the 3′-UTR of SPRY4-IT1. Moreover, SPRY4-IT1 was found to bind STAU1, promote STAU1 recruitment to the 3′-UTR of TCEB1 mRNA, and affect TCEB1 mRNA stability and expression, resulting in hypoxia-inducible factor 1α (HIF-1α) upregulation, and thereby affecting cancer cell metastasis. In addition, STAU1 depletion abrogated TCEB1 SMD and alleviated the pro-metastatic effect of SPRY4-IT1 overexpression. Significantly, we revealed that SPRY4-IT1 is also transactivated by NF-κB/p65, which activates SPRY4-IT1 to inhibit TCEB1 expression, and subsequently upregulate HIF-1α. In conclusion, our results highlight a novel mechanism of cytoplasmic lncRNA SPRY4-IT1 in which SPRY4-IT1 affecting TCEB1 mRNA stability via STAU1-mediated degradation during cancer metastasis.