CASC19 stabilization by ALYREF via m5C modification and its impact on SCD in colorectal cancer cell aggressiveness and stemness

The progression of colorectal cancer (CRC) is closely associated with aberrant epigenetic regulation. As a key regulator of m5C modification, the role and mechanism of Aly/REF export factor (ALYREF) in CRC remain unclear. This study aims to elucidate the molecular mechanism by which ALYREF regulates the long non-coding RNA cancer susceptibility 19 (CASC19) through m5C modification and its impact on CRC malignancy. In this study, ALYREF was significantly upregulated in CRC tissues and cell lines and was associated with poor patient prognosis. Mechanistically, ALYREF recruited the m5C methyltransferase NOP2/Sun RNA Methyltransferase 2 (NSUN2) to modify the 3'UTR of CASC19, thereby enhancing its stability. CASC19, in turn, recruited Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) to form a complex that stabilized stearoyl-CoA desaturase (SCD) mRNA, ultimately promoting CRC cell proliferation, metastasis, and stemness. In vivo experiments demonstrated that ALYREF knockdown suppressed tumor growth and lung metastasis, while SCD overexpression reversed the tumor-suppressive effects of CASC19 knockdown. In Conclusion, this study unveils the pivotal regulatory role of the ALYREF/m5C/CASC19/HNRNPC/SCD axis in CRC, providing a novel therapeutic target for disrupting RNA epigenetic-metabolic interactions in cancer treatment.