TCF3/ACSS2 Axis Promotes Proliferation and Colony-Forming Capacity of Esophageal Squamous Cell Carcinoma Cells
TCF3/ACSS2 Axis Promotes Proliferation and Colony-Forming Capacity of Esophageal Squamous Cell Carcinoma Cells
Hongqi Li1 and Meidong Xu1,2*
ABSTRACT
Esophageal carcinoma (ESCA), particularly esophageal squamous cell carcinoma (ESCC), is a prevalent and challenging health problem. Recent investigations have identified various transcription factors implicated in ESCC tumorigenesis and cancer progression, with potentials to serve as promising therapeutic targets. This study aimed at identifying novel therapeutic targets, particularly transcription factors and downstream effectors associated with ESCC pathogenesis. Data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were analyzed, and the functional significance of transcription factor 3 (TCF3) in regulating ESCC aggressiveness was further studied. TCF3 was knocked down or overexpressed to investigate the ESCC cell proliferation and colony-forming capacity. RNA sequencing was performed to explore downstream effectors of TCF3. Moreover, acyl-CoA short-chain synthetase family member 2 (ACSS2) knockdown and overexpression was conducted to further examine ESCC cell proliferation and colony-forming capacity. Mouse xenograft models were utilized to access the influence of ACSS2 on ESCC tumor growth in vivo. The results revealed that, TCF3 was significantly elevated in ESCA tumors and associated with the of ESCA patient prognosis. TCF3 silencing suppressed ESCC colony-forming capacity and cell proliferation, in contrast, overexpression of TCF3 prominently accelerated ESCC cell proliferation and colony formation. Mechanistically, ACSS2 is a critical nucleocytosolic enzyme that converses acetate to acetyl-CoA, and acts as a TCF3 downstream molecule. TCF3 modulates the aggressiveness of ESCC by regulating the levels of ACSS2. In consistence, ACSS2 knockdown also attenuated ESCC colony-forming capacity and proliferation, while ACSS2 overexpression promoted these two phenotypes. In addition, ACSS2 knockdown cells formed significantly smaller tumors in mouse xenograft models, indicating ACSS2 as an attractive anti-cancer treatment target. In conclusion, this research identified the functional importance of TCF3/ACSS2 axis in regulating ESCC cancer progression and supported it as an attractive treatment option for ESCC treatment.
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