Abstract
In this study, we investigated the mechanistic role and prognostic significance of the long coding RNA (lncRNA) KCNQ1OT1 in colorectal cancer (CRC). KCNQ1OT1 levels were significantly higher in CRC tissues than adjacent normal colorectal tissues (n=79). High KCNQ1OT1 expression correlated with poorer prognosis in CRC patients. KCNQ1OT1-silenced CRC cells showed reduced proliferation, colony formation, extracellular acidification, and lactate and glucose secretion. This suggests KCNQ1OT1 promotes CRC cell proliferation by increasing aerobic glycolysis. RNA pull-down assays with biotinylated KCNQ1OT1 followed by mass spectrometry analysis showed that KCNQ1OT1 directly binds to hexokinase 2 (HK2). This was confirmed by RNA immunoprecipitation assays using anti-hexokinase 2 antibody. HK2 protein levels were reduced in KCNQ1OT1 knockdown CRC cells, but were restored by treatment with the proteasomal inhibitor MG132. KCNQ1OT1 knockdown CRC cells also showed higher ubiquitinated-HK2 levels, suggesting KCNQ1OT1 enhances aerobic glycolysis by stabilizing HK2. HK2 overexpression in KCNQ1OT1 knockdown CRC cells restored proliferation and aerobic glycolysis. KCNQ1OT1 levels correlated positively with HK2 expression and prognosis in CRC patients. These findings show that KCNQ1OT1 promotes colorectal carcinogenesis by increasing aerobic glycolysis through HK2.
Highlights
Colorectal cancer is one of the most malignant tumors worldwide
Quantitative real time PCR analyses showed that KCNQ1OT1 expression was significantly higher in colorectal cancer samples compared to adjacent normal colorectal tissues (n=79; Figure 1A)
We analyzed the relationship between long coding RNA (lncRNA) KCNQ1OT1 expression and survival outcomes in colorectal cancer patients
Summary
Colorectal cancer is one of the most malignant tumors worldwide. Despite technological advances in diagnostic and treatment modalities, the prognosis of colorectal cancer patients remains poor because a large number of patients are diagnosed when the cancer has already advanced and are not amenable for surgical resection [1,2,3]. There is an urgent need to identify target genes that can reliably indicate the prognosis of patients with colorectal cancer Cancer cells alter their metabolism in order to survive and grow in a highly hypoxic and nutrient-deficient tumor microenvironment [8,9,10]. It is well documented that cancer cells rewire their metabolism and breakdown glucose to lactate in the presence of oxygen (aerobic glycolysis), a phenomenon called as the Warburg effect [11,12,13]. This metabolic reprogramming involves altered expression and post-translational modification of several key metabolic enzymes [14]. The www.aging-us.com molecular mechanisms underlying the altered expression or post-translational modifications of key metabolic proteins in tumors are yet to be fully understood
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