Specific activation of glycolytic enzyme enolase 2 in BRAF V600E‐mutated colorectal cancer

Abstract

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E‐mutated tumors via in silico analysis using a large‐scale clinical database. We found that BRAF V600E‐mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E‐mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E‐mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild‐type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E‐mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP‐1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E‐mutated CRC and indicate the therapeutic implications of targeting this gene.

Increased Expression of NXPH4 Correlates with Immune Cell Infiltration and Unfavorable Prognosis in Hepatocellular Carcinoma

“…The results demonstrated that NXPH4 was positively related with the top coexpressed genes (PKM2, ENO2, SLC16A3, SAPCD2, and PNCK), and all these genes were associated with poor survival of HCC. PKM, ENO2, and SLC16A3 have been researched to have important effects on promoting tumor progression [22][23][24][25][26]. Based on the GO and KEGG pathway analyses, it was suggested that the NXPH4 coexpressed genes play important roles in metabolism and intracellular signaling transduction.…”

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

“…ENO2 can function as on oncogene, either in neuronal malignancies or in other cancer types, such as lung, breast, and prostate cancer [96-98]. Recent evidence was provided that the C-term domain of ENO2, which is not necessary for metabolic activity, activates the MAPK/ERK signaling pathway and thus promotes proliferation and migration of BRAV V600E-mutated CRC cells [99]. In this regard, in our study, we demonstrate that the combined knockdown of ALDOC and ENO2 signi cantly reduced lactate production and consequently attenuated the sphere-forming ability of both LUAD and breast cancer cell lines both in nutrient-rich and nutrient-restricted conditions.…”

ENO2 Promotes Colorectal Cancer Metastasis by Interacting with the LncRNA CYTOR and Activating YAP1-Induced EMT

“…ENO2 is an important member of the enolase family, which catalyzes the synthesis of phosphoenolpyruvate (PEP) to mediate glycolysis and gluconeogenesis [ 10 ]. Some studies have suggested that ENO2 promotes metastasis by activating and enhancing glycolysis [ 11 , 12 , 13 ], while others have attributed this promotion to non-glycolytic pathways [ 14 ]. Muller et al first showed that inhibition of ENO2 by the homozygous deletion of ENO1 selectively suppressed the growth and tumorigenic potential of glioblastoma cells [ 15 ].…”