Abstract 6703: LncRNA UCA1 modulates LDHA expression and drives glucose metabolism in colorectal cancer cells

Abstract Background: Colorectal cancer (CRC) ranks as the third most commonly diagnosed malignancy globally and is the second leading cause of cancer-related deaths in the United States. In 2024, an estimated 152, 810 new cases of CRC are projected, with 53, 010 fatalities. The prognosis for metastatic CRC (mCRC) remains grim, with a survival rate of less than 15%. Urothelial cancer-associated 1 (UCA1), a long noncoding RNA (lncRNA), is dysregulated in CRC and has been implicated in tumor progression. Our research highlights significantly elevated UCA1 expression in metastatic CRC cells, where its association with the GLUT1 and the metabolic enzyme lactate dehydrogenase A (LDHA) suggests a critical role in promoting the Warburg effect—a metabolic hallmark of cancer. Methods: To evaluate the oncogenic phenotype, assays for migration, invasion, colony formation, and proliferation were conducted. Lentiviral vectors with puromycin selection were used to generate UCA1 overexpression and knockdown cell lines, and fluorescence-activated cell sorting (FACS) was performed to enrich GFP-expressing cells. Anoikis resistance was induced using PolyHEMA plates, and glucose metabolism markers were analyzed at specific time points through RT-PCR and western blotting. Immunofluorescence was used to assess the localization and expression of relevant proteins. Metabolic assays were performed using the Seahorse xFp. Results: Metastatic CRC cells (SW620) exhibited significantly higher UCA1 expression compared to oncogenic CRC cells (SW480), particularly after 36 hours of anoikis induction. Enhanced expression of GLUT1, YAP1, and FDFT1 was also observed in SW620 cells. UCA1 overexpressing cell line (SW480+UCA1) also showed enhanced expression of GLUT1, YAP1, and FDFT1 correlating with glucose metabolism modulation during anoikis. The expression of LDHA, a key enzyme in the Warburg effect that converts pyruvate to lactate despite oxygen availability, was markedly elevated in SW620 cells compared to SW480 cells. Similarly, LDHA expression was significantly higher in UCA1-overexpressing SW480 cells compared to vector controls. This suggests a functional link between UCA1 and LDHA in metastatic CRC, supported by published studies linking LDHA with GLUT1 and YAP1. Conclusion: These findings underscore the pivotal role of lncRNA UCA1 in regulating LDHA expression and driving glucose metabolism via the Warburg effect during anoikis resistance, a critical step in metastasis. Targeting the UCA1-LDHA axis may offer novel therapeutic opportunities for combating metastatic CRC. Citation Format: Salique H. Shaham, Ricardo Pequeno Bracho, Manish K. Tripathi. LncRNA UCA1 modulates LDHA expression and drives glucose metabolism in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6703.