LncRNA UCA1 regulates LDHA expression to drive Warburg metabolism and colorectal cancer progression

Background : Colorectal cancer (CRC) is the third most common malignancy worldwide and the second leading cause of death in the US. In 2025, an estimated 154,270 new cases of colon cancer will be diagnosed. In the US, colorectal cancer ranks as the second most common cause of cancer-related deaths, with an expected 52,900 deaths in 2025. Urothelial cancer-associated 1 (UCA1), a long noncoding RNA (lncRNA), has been found to be dysregulated in CRC and to promote tumor growth. Unlike carcinogenic colon cells, we have observed that the lncRNA UCA1 is significantly expressed in metastatic CRC cells. Its expression is also linked to glucose metabolism factors, including glucose transporter 1 (Glut1) and lactate dehydrogenase (LDHA). LDHA is essential for the rapid production of ATP in cancer cells, thereby supporting their progression. Methods: Cell migration, invasion, and proliferation assays were conducted on isogenic CRC cells (SW480 and SW620), as well as on cells overexpressing UCA1 (SW480+UCA1; OE) and those with UCA1 knockdown (SW620+shUCA1; KD). Anoikis induction was examined using the isogenic, OE, and KD cell lines. RT-PCR, Western blot, and immunofluorescence techniques were employed for RNA and protein analysis of YAP1, Glut1, and LDHA. Glucose and lactose levels in CRC cells were also assessed. Results: LncRNA UCA1 showed significantly higher expression in metastatic CRC (SW620) cells compared to carcinogenic CRC (SW480) cells. After 36 hours under anoikis conditions, UCA1 expression became exponentially higher. UCA1 levels, along with Glut1 and YAP1, are also elevated in metastasis (SW620 cells) compared to carcinogenic (SW480 cells). In UCA1-overexpressing SW480 cells, the gene expression levels of Glut1 and YAP1 increased significantly, indicating that UCA1 plays a role in regulating glucose metabolism. In the Warburg effect, cancer cells convert Pyruvate into lactate even in the presence of oxygen, rather than using it for the TCA cycle. We found that the gene expression of LDHA, the enzyme converting pyruvate to lactate, was significantly higher in metastatic CRC cells compared to carcinogenic CRC cells. UCA1-overexpressing cells also showed significantly increased LDHA expression, suggesting that UCA1 influences LDHA enzyme activity. LDHA correlated with GLUT1 and YAP1, highlighting the crucial role of LDHA during Warburg glucose metabolism and CRC cell progression. Inhibiting LDHA reduces Glut1 levels within the cell and limits tumor cell growth.