Superenhancer drives a tumor-specific splicing variant of MARCO to promote triple-negative breast cancer progression
| Autor: | Yun-Song Yang, Xi Jin, Qin Li, Yi-Yu Chen, Fenfang Chen, Hena Zhang, Ying Su, Yi Xiao, Gen-Hong Di, Yi-Zhou Jiang, Shenglin Huang, Zhi-Ming Shao |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 119 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The transcription variation, leading to various forms of transcripts and protein diversity, remains largely unexplored in triple-negative breast cancers (TNBCs). Here, we presented a comprehensive analysis of RNA splicing in breast cancer to illustrate the biological function and clinical implications of tumor-specific transcripts (TSTs) arising from these splicing junctions. Aberrant RNA splicing or TSTs were frequently harbored in TNBC and were correlated with a poor outcome. We discovered a tumor-specific splicing variant of macrophage receptor with collagenous structure–TST (MARCO-TST), which was distinguished from myeloid cell-specific wild-type MARCO. MARCO-TST expression was associated with poor outcomes in TNBC patients and could promote tumor progression in vitro and in vivo. Mechanically, MARCO-TST interacted with PLOD2 and enhanced the stability of HIF-1α, which resulted in the metabolic dysregulation of TNBC to form a hypoxic tumor microenvironment. MARCO-TST was initiated from a de novo alternative transcription initiation site that was activated by a superenhancer. Tumors with MARCO-TST expression conferred greater sensitivity to bromodomain and extraterminal protein inhibitors. This treatment strategy was further validated in patient-derived organoids. In conclusion, our results revealed the transcription variation landscape of TNBC, highlighting MARCO-TST as a crucial oncogenic transcript and therapeutic target. |
| Databáze: | OpenAIRE |
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