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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306470 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H). This model is described in the article: Computational Modelling of the Metabolic States Regulated by the Kinase Akt. Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L. Frontiers in Systems Biology. 2012 Oct 13 Abstract: Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism. This model is hosted on BioModels Database and identified by: MODEL1210150000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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

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