LncRNA ELFN1-AS1 maintains the stemness of colorectal cancer by preventing ubiquitinated degradation of the hnRNPA1 protein.

Cancer stem cells (CSCs) are closely related to tumor drug resistance, recurrence, and metastasis, presenting significant challenges in cancer treatment. Although numerous long noncoding RNAs (lncRNAs) have been implicated in colorectal cancer (CRC), only a few have been reported to regulate cancer stemness. The lncRNA ELFN1-AS1 is known to play a crucial role in CRC development; however, its function in maintaining cancer stemness remains uncertain. In this study, we established colorectal cancer stem cell-like (CSC-like) cells enrichment models using human SW620 and HCT116 cell lines and found that ELFN1-AS1 was significantly overexpressed in CD44(+)CD133(+) CSC-like cells. Functional assays, including cell spheroid formation, colony formation, and subcutaneous tumor transplantation, demonstrated that ELFN1-AS1 knockdown effectively suppressed tumorigenic capacity. Limiting dilution assays, both in vitro and in vivo, further validated the critical role of ELFN1-AS1 in tumor initiation. Mechanistic investigations, including RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), and colocalization staining, revealed that ELFN1-AS1 directly interacts with hnRNPA1 in the nucleus of CSC-like cells. ELFN1-AS1 promoted the expression of downstream proteins CD44v6 and PKM2 by competitively binding to hnRNPA1, thereby inhibiting the interaction between the E3 ubiquitin ligase β-TrCP and hnRNPA1. Our findings demonstrated that ELFN1-AS1 facilitated CRC malignancy by maintaining and enhancing tumor cell stemness, suggesting that targeting ELFN1-AS1 may represent a potential therapeutic strategy for CRC.