CUEDC1 promotes glycolytic metabolism reprogramming through the CUEDC1/CACNG4/PI3K axis to promote ER-positive breast cancer growth

Background The reprogramming of energy metabolism, particularly glycolysis, upholds the malignancy of tumors. The relationship between CUE Domain Containing protein-1 (CUEDC1) and glycolysis, along with its influence on the development of ER-positive breast cancer (ER+ BRCA), is not well defined. This investigation explores the functional involvement of CUEDC1 in glycolysis regulation and uncovers a previously unidentified pathway contributing to the progression of ER+ BRCA. Methods Immunohistochemistry, western blotting and qRT-PCR were used to detect the expression of CUEDC1 in ER+ BRCA tissues and cell lines. A series of molecular analyses, including dual-luciferase reporter assays, RNA-seq, and ChIP, were performed to elucidate the potential mechanisms underlying CUEDC1’s involvement in ER+ BRCA progression. Metabolic assays focusing on glycolysis were employed to investigate the functional roles of CUEDC1 and Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 4 (CACNG4). The Connectivity Map (CMap) database was utilized to screen CUEDC1 inhibitors. Results CUEDC1 is aberrantly upregulated in ER+ BRCA tissues and cells. Increased CUEDC1 can promote enhanced tumor growth and lead to poor clinical outcomes in ER+ BRCA patients. The MYC associated zinc finger protein (MAZ) can up-regulate CUEDC1 gene transcription in ER+ BRCA cells by directly binding to its promoter. We determined that CUEDC1 directly modulated CACNG4 to enhance PI3K/AKT pathway activation, thereby facilitating tumor growth of ER+ BRCA. Clinical observations also revealed a positive correlation between CACNG4 expression and CUEDC1, with both factors being strongly associated with poor prognosis in ER+ BRCA patients. Mechanistically, The CUEDC1/CACNG4/PI3K signal axis enhanced glycolysis through upregulating GLUT1, a crucial protein in glucose metabolism, thereby supporting tumor growth of ER+ BRCA. Furthermore, methotrexate was identified as a potential inhibitor of CUEDC1. Importantly, the combination of Ipatasertib (a PI3K/AKT pathway inhibitor), with methotrexate effectively suppressed growth of ER+ BRCA in a mouse model. Conclusions Our research reveals that the enhanced CUEDC1 is intricately linked to the proliferation of ER+ BRCA. CUEDC1-driven CACNG4 expression stimulates PI3K/AKT pathway activity and its downstream signaling, which facilitates tumor progression and positions CUEDC1-driven glycolysis as a key therapeutic target in addressing this malignancy.