Long noncoding RNA KCNQ1OT1 promotes colorectal carcinogenesis by enhancing aerobic glycolysis via hexokinase-2

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.

Long Noncoding RNA KCNQ1OT1 is a Prognostic Biomarker and mediates CD8+ T cell exhaustion by regulating CD155 Expression in Colorectal Cancer

“…CD155 (PVR/Necl5/Tage4) is a member of the nectin-like adhesion molecule family, which is highly upregulated on tumor cells of many cancer types and is associated with poor patient prognosis [27]. CD155 regulates the function of tumor infiltrating lymphocytes by interacting with stimulatory and inhibitory receptors such as TIGIT on T cells and NK cells [38,39]. As a miRNA sponge, lncRNA KCNQ1OT1 can promote immune evasion by upregulating PD-L1 expression in prostate cancer and regulating immune escape in sorafenib-resistant hepatoma carcinoma cell cells [40,41].…”

Cancer Susceptibility Candidate 9 (CASC9) Promotes Colorectal Cancer Carcinogenesis via mTOR-Dependent Autophagy and Epithelial–Mesenchymal Transition Pathways

“…For instance, UNC5B antisense lncRNA 1 (UNC5B-AS1) has been shown to reduce apoptosis, accelerate CRC progression, and result in metastasis (Zhang Y. et al, 2020). Liu et al (2020) illustrated that higher expression of KCNQ1OT1 promotes CRC Abbreviations: AMPK, AMP-activated protein kinase; ATCC, American Type Culture Collection; CASC9, Cancer susceptibility candidate 9; COAD, Colon adenocarcinoma; CRC, Colorectal cancer; DMEM, Dulbecco modified eagle medium; Dsi-CASC9, Dicer-substrate mediated CASC9; Dsi-NC, Dicer-substrate negative control; EMT, Epithelial-mesenchymal transition; ENCORI, The Encyclopedia of RNA Interactomes; FBS, Fetal bovine serum; HR, Hazard ratio; IDT, Integrated DNA technologies; lncRNAs, Long non-coding RNAs; ncRNAs, Non-coding RNAs; qRT-PCR, Quantitative reverse transcriptase-polymerase chain reaction; TCGA, The Cancer Genome Atlas; TPM, Transcript per million; UNC5B-AS1, The UNC5B antisense lncRNA 1. carcinogenesis by enhancing aerobic glycolysis and stabilization of hexokinase 2 gene (Chen C. et al, 2020). Likewise, FOXC2-AS1 promoted CRC progression via stabilizing FOXC2 and Ca 2+ channel-controlled FAK signaling pathway (Pan and Xie, 2020).…”

“…For instance, UNC5B antisense lncRNA 1 (UNC5B-AS1) has been shown to reduce apoptosis, accelerate CRC progression, and result in metastasis ( Zhang Y. et al, 2020 ). Liu et al (2020) illustrated that higher expression of KCNQ1OT1 promotes CRC carcinogenesis by enhancing aerobic glycolysis and stabilization of hexokinase 2 gene ( Chen C. et al, 2020 ). Likewise, FOXC2-AS1 promoted CRC progression via stabilizing FOXC2 and Ca 2+ channel–controlled FAK signaling pathway ( Pan and Xie, 2020 ).…”

Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

“…The role of several long noncoding RNAs (lncRNAs) was also described in inhibition of Warburg effect in CRCs [ 33 , 259 , 260 ]. These included maternally expressed gene 3 (MEG3) lncRNA, overexpression of which inhibited glycolysis, as well as reduced lactate production in CRC cells.…”