Abstract
C-Myc overexpression contributes to multiple hallmarks of human cancer but directly targeting c-Myc is challenging. Identification of key factors involved in c-Myc dysregulation is of great significance to develop potential indirect targets for c-Myc. Herein, a collection of long non-coding RNAs (lncRNAs) interacted with c-Myc is detected in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, lncRNA BCAN-AS1 is identified as the one with highest c-Myc binding enrichment. BCAN-AS1 was abnormally elevated in PDAC tumors and high BCAN-AS1 level was significantly associated with poor prognosis. Mechanistically, Smad nuclear-interacting protein 1 (SNIP1) was characterized as a new N6-methyladenosine (m6A) mediator binding to BCAN-AS1 via recognizing its m6A modification. m6A-modified BCAN-AS1 acts as a scaffold to facilitate the formation of a ternary complex together with c-Myc and SNIP1, thereby blocking S phase kinase-associated protein 2 (SKP2)-mediated c-Myc ubiquitination and degradation. Biologically, BCAN-AS1 promotes malignant phenotypes of PDAC in vitro and in vivo. Treatment of metastasis xenograft and patient-derived xenograft mouse models with in vivo-optimized antisense oligonucleotide of BCAN-AS1 effectively represses tumor growth and metastasis. These findings shed light on the pro-tumorigenic role of BCAN-AS1 and provide an innovant insight into c-Myc-interacted lncRNA in PDAC.
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Data availability
C-Myc RIP-seq, RNA-seq and SNIP1 CLIP-seq raw data generated in this study are publicly available in the Gene Expression Omnibus at GSE181777. miCLIP sequencing data have been deposited in the NCBI Short Read Archive with the BioProject ID-PRJNA693621. All custom code used to generate the data in this study is available upon reasonable request.
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Acknowledgements
This study was supported by the National Key R&D Program of China (2021YFA1302100 to J. Zheng), National Natural Science Foundation of China (82325037, 82072617 to J. Zheng and 82003162 to J. Zhang), Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2017ZT07S096 to D.L.), China Postdoctoral Science Foundation (2023M734042 to J.S.) and Sun Yat-sen University Intramural Funds (to D.L. and to J. Zheng).
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J. Zheng and J. Zhang conceptualized and supervised this study. G.W., J.S. and L. Zeng performed most experiments. S.D., Y.Y. and R.L. conducted statistical and bioinformatics analyses. J. Zhang and X.H. performed animal experiments. Q.Z., Y.Z., J.D., S.Z. and R.C. contributed to collection of clinic samples. M.L. contributed to histopathological analyses. R.B. and L. Zhuang provided technique supports. G.W. J.S., J. Zheng and D.L. prepared manuscript. All authors reviewed the manuscript.
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This study was approved by the Institutional Review Board of the Sun Yat-sen Memorial Hospital and Chinese Academy of Medical Sciences Cancer Hospital. All animal experiments were approved by the Institutional Animal Care and Use Committee of the Sun Yat-sen University Cancer Center and the animals were handled in accordance with institutional guidelines.
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Wu, G., Su, J., Zeng, L. et al. LncRNA BCAN-AS1 stabilizes c-Myc via N6-methyladenosine-mediated binding with SNIP1 to promote pancreatic cancer. Cell Death Differ 30, 2213–2230 (2023). https://doi.org/10.1038/s41418-023-01225-x
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DOI: https://doi.org/10.1038/s41418-023-01225-x