FBXW7 negatively regulates ENO1 expression and function in colorectal cancer

Abstract

FBXW7 (F-box and WD40 domain protein 7) is a tumor suppressor frequently inactivated in human cancers. The precise molecular mechanisms by which FBXW7 exerts antitumor activity remain under intensive investigation and are thought to relate in part to FBXW7-mediated destruction of key cancer-relevant proteins. Enolase 1 (ENO1) possesses oncogenic activity and is often overexpressed in various human cancers, besides its critical role in glycolysis. However, the detailed regulatory mechanisms of ENO1 expression remain unclear. Here we show that the elevated expression of ENO1 was identified in FBXW7-depletion HCT116 cells through two-dimensional protein electrophoresis and mass spectrometry assays (2DE-MS). Subsequent western blotting and immunohistochemical assays confirmed that ENO1 expression reversely correlates with FBXW7 expression in several cells and colon cancer tissues. Furthermore, we show that FBXW7 physically binds to ENO1 and targets ENO1 for ubiquitin-mediated degradation. Functionally, we found that FBXW7 suppresses the ENO1-induced gene expression, lactate production, cell proliferation and migration. These findings suggest that ENO1 is a novel substrate of FBXW7, and its activity can be negatively regulated by FBXW7 at the posttranslational level. Our work provides a novel molecular insight into FBXW7-directed tumor suppression through regulation of ENO1.

Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma

“…For example, pyruvate kinase M2 (PKM2) facilitates colon cancer cell migration and drug resistance via the modulation of STAT3 signal [13,14]. Alpha-enolase (ENO1) promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway [15], and ENO1 is confirmed as a novel substrate of FBXW7 in colorectal cancer [16]. Lactate dehydrogenase A (LDHA) acts as oncogenic role in prostate cancer [17].…”

Genome-wide Analysis of WD40 Protein Family in Human

“…Further mining of these data with careful curation and robust algorithms in the future will greatly improve our understanding of this gene family, especially for those datasets with disease and normal tissue comparisons. Previous studies have reported many WD40 genes involved in different human diseases, such as cancer and neurodegenerative diseases141517373839. Studies on their biological roles in disease pathogenesis will be an important direction in the future.…”

“…Consistent with their essential roles, many are involved in various diseases. For example, FBXW7 is a well-known tumour suppressor and is implicated in several cancers1415. TLE1 is also a well-studied tumour suppressor gene16.…”

Emerging Roles for Noncanonical NF-κB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology

“…The inactivation of FBXW7 at the cellular level was shown to result in elevated p100 levels, and may therefore be interpreted as an increase in non-canonical NF-κB activity (135). Despite the fact that there is currently no evidence in the literature evaluating its involvement in IBD, some data have concluded that FBXW7 is downregulated in gastric cancer (136) and is inversely correlated with the tumor promoter ENO1 in colorectal cancer (137). In addition to TNAP and FBXW7, an assortment of other miscellaneous molecules have been shown to bind to NIK including epidermal growth factor (EGF) and its receptor (EGFR) (138), caspase death domains (139) and the protein of the proto-oncogene Cot/Tpl-2 (140), although only the effects on the canonical NF-κB pathway has been fully characterized for these additional proteins.…”