Abstract
Breast cancer is a leading cause of death in women worldwide, but the underlying mechanisms of breast tumorigenesis remain unclear. Fructose-1, 6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor in breast cancer. However, the mechanisms of FBP1 as a tumor suppressor in breast cancer remain to be explored. Here we showed that FBP1 bound to Notch1 in breast cancer cells. Moreover, FBP1 enhanced ubiquitination of Notch1, further leading to proteasomal degradation via FBXW7 pathway. In addition, we found that FBP1 significantly repressed the transactivation of Notch1 in breast cancer cells. Functionally, Notch1 was involved in FBP1-mediated tumorigenesis of breast cancer cells in vivo and in vitro. Totally, these findings indicate that FBP1 inhibits breast tumorigenesis by regulating Notch1 pathway, highlighting FBP1 as a potential therapeutic target for breast cancer. IMPLICATIONS: We demonstrate FBP1 as a novel regulator for Notch1 in breast cancer.
Highlights
Reprogramming metabolism is a hallmark of cancer, and maintains glucose homeostasis that is balanced by the catabolic glycolysis and anabolic gluconeogenesis pathways [1]
FBP1 is a novel binding partner of Notch1 As described previously, FBP1 as tumor suppressor can modulate the activity of Hif-1a via physical interaction [11]
FBP1 as a tumor suppressor played a crucial role in regulating gluconeogenesis and glycolysis, which is highly expressed in multiple cancers [32]
Summary
Reprogramming metabolism is a hallmark of cancer, and maintains glucose homeostasis that is balanced by the catabolic glycolysis and anabolic gluconeogenesis pathways [1]. The key role of FBP1 in cancer is as an enzyme, and as a coactivator for transcription factors to regulate target genes' expression. Modulator of the IQGAP1–MAPK signaling axis in pancreatic ductal adenocarcinoma cells, and binding to the WW domain of IQGAP1 impedes IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity [9], but the mechanisms of FBP1 as noncanonical functions of enzymes are still not fully understood in cancer. The activated Notch receptor functions as an oncogene to regulate breast tumorigenesis and increased expression of Notch and its ligand Jagged-1 predicts poorer overall survival for women with breast cancer [20]. We demonstrate that FBP1 is a crucial regulator of breast cancer tumorigenesis due to its interaction with Notch. Our study uncovers a rationale for the use of a FBP1/Notch pathway as the potential target for therapeutic intervention in breast cancer
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