Squalene synthase predicts poor prognosis in stage I-III colon adenocarcinoma and synergizes squalene epoxidase to promote tumor progression.

Abstract

Colon adenocarcinoma (COAD) is one of the most prevalent malignancies, with poor prognosis and lack of effective treatment targets. Squalene synthase (FDFT1) is an upstream enzyme of squalene epoxidase (SQLE) in cholesterol biosynthesis. In a previous study, we revealed that SQLE promotes colon cancer cell proliferation in vitro and in vivo. Here, we investigate the prognostic value of FDFT1 in stage I-III COAD and explore the potential underlying mechanisms. Squalene synthase was significantly upregulated in stage I-III COAD and positively correlated with poor differentiation and advanced tumor stage. High expression of FDFT1 was an independent predictor of overall and relapse-free survival, and the nomograms based on FDFT1 could effectively identify patients at high risk of poor outcome. Squalene synthase accelerated colon cancer cell proliferation and promoted tumor growth. Lack of FDFT1 resulted in accumulating NAT8 and D-pantethine to lower reactive oxygen species levels and inhibit colon cancer cell proliferation. Moreover, the combined inhibition of FDFT1 and SQLE induced a greater suppressive effect on cell proliferation and tumor growth than single inhibition. Taken together, these results indicate that FDFT1 predicts poor prognosis in stage I-III COAD and has the tumor-promoting effect on COAD through regulating NAT8 and D-pantethine. Targeting both FDFT1 and SQLE is a more promising therapy than their single inhibition for stage I-III COAD.

• Authors: Huihong Jiang, Erjiang Tang, Ying Chen, Hailong Liu, Yun Zhao, Moubin Lin, Luwei He
• Journal: Cancer science (Cancer Sci) Vol. 113 Issue 3 Pg. 971-985 (Mar 2022) ISSN: 1349-7006 [Electronic] England
• PMID: 34939274 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Reactive Oxygen Species
• Pantetheine
• pantethine
• Squalene Monooxygenase
• Acetyltransferases
• NAT8 protein, human
• Farnesyl-Diphosphate Farnesyltransferase

Topics

• Acetyltransferases (metabolism)
• Aged
• Aged, 80 and over
• Animals
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms (enzymology, metabolism, pathology)
• Farnesyl-Diphosphate Farnesyltransferase (deficiency, metabolism)
• Female
• Humans
• Male
• Mice
• Middle Aged
• Neoplasm Staging
• Pantetheine (analogs & derivatives, metabolism)
• Prognosis
• Reactive Oxygen Species (metabolism)
• Squalene Monooxygenase (deficiency, metabolism)
• Xenograft Model Antitumor Assays