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LncRNA BCAR4 promotes tumorigenesis in triple-negative breast cancer by stabilizing the MYC-WDR5 complex
Yiqing Xi1,2, Zun Zhang1, Yuxia Duan3
1Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Abstract:
Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) characterized by relatively high MYC amplification and poor prognosis. Long non-coding RNAs (lncRNAs) play critical roles in various cancer types; however, their precise roles in regulating MYC function and driving TNBC progression remain to be fully elucidated. In the present study, we demonstrate that the lncRNA BCAR4 is highly expressed in TNBC tissues and negatively correlates with clinical prognosis in TNBC patients. BCAR4 is mainly localized to the nucleus and promotes cell migration and invasion in TNBC cells. Mechanistically, BCAR4 binds to the MBIII domain of MYC and acts as a modular scaffold to stabilize the MYC-WDR5 complex. This stabilization, in turn, enhances MYC chromatin enrichment and downregulates the expression of MYC target genes, with TXNIP, a tumor suppressor gene, as a representative example. Notably, ectopic expression of TXNIP abrogates the pro-tumor progression effect of BCAR4, which is dominated by invasion and metastasis, and sensitizes TNBC cells to bromodomain and extra-terminal (BET) inhibitor treatment. Our findings not only identify BCAR4 as a functionally important lncRNA in TNBC but also provide insights into the development of novel therapeutic strategies.
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