Tumor-enriched circRNA TAFCR1 drives cancer progression and metastasis by disrupting UBE1-dependent TRIM21-mediated CD44 ubiquitination

Lipid metabolic reprogramming is a hallmark of cancer, driving tumorigenesis, progression, metastasis, and chemoresistance. Fatty acid synthase (FASN) is a key enzyme in this pathway. Here, we identified a novel exonic circular RNA (circRNA) within the FASN locus, termed TAFCR1 (tumor-associated FASN circular RNA 1). TAFCR1 comprises partial exon 20 (20 L), exons 21, 22, and partial 23 (23 S) of the FASN gene, generated through MBNL1-mediated back-splicing via short Alu motifs at the cyclization junction. TAFCR1 was tumor-specifically upregulated and promoted proliferation, invasion, and migration of cancer cells in vitro. In vivo, TAFCR1 knockdown suppressed tumor growth and metastasis, and prolonging survival in xenograft and lung metastasis models. Mechanistically, TAFCR1 functions as a specific RNA modulator that binds the ubiquitin-activating enzyme E1 (UBE1/UBA1), thereby disrupting UBE1-dependent, TRIM21-mediated CD44 ubiquitination and upregulating the oncogenic signaling molecule CD44. The E3 ubiquitin ligase TRIM21 serves as a critical mediator regulating CD44 ubiquitination by binding to the CD44 intracellular domain (CD44-ICD) and catalyzing K48-linked polyubiquitination of CD44 at K695. Upregulated CD44 further activates the PI3K/AKT pathway by suppressing the tumor suppressor PHLPP1. This cascade subsequently enhances the expression of stemness factor SOX2, epithelial-mesenchymal transition (EMT) markers (vimentin, N-cadherin, and fibronectin), and matrix metalloproteinase-9 (MMP9), ultimately promoting cancer metastasis. Collectively, our findings establish TAFCR1 as a promising therapeutic target for cancers.