Int J Biol Sci 2023; 19(6):1925-1940. doi:10.7150/ijbs.76704 This issue Cite
1. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
2. College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
3. Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
4. School of Medicine Chongqing University, Chongqing 400030, China.
*These authors contributed equally to this work.
Background: Fatty acid oxidation (FAO) is a major alternate energy metabolism pathway in tumor cells subjected to metabolic stress caused by glucose deficiency during rapid progression. However, the mechanism of metabolic reprogramming between glycolysis and FAO in tumor cells is unknown. Therefore, identifying the metabolic glucolipid conversion hub in tumor cells is crucial.
Methods: We used single-cell RNA sequencing (scRNA-Seq), RNA sequencing (RNA-Seq), The Cancer Genome Atlas (TCGA), and chromatin immunoprecipitation sequencing (ChIP-Seq) to predict the critical regulator and mechanism of metabolic glucolipid conversion in colorectal cancer (CRC) tumor cells. We used Seahorse metabolic analysis, immunoblotting, immunofluorescence, and immunohistochemical (IHC) technology to verify the prediction and mechanism of this regulator in cancer cell lines, a nude mouse xenograft model, and clinical CRC samples.
Results: We demonstrated that sirtuin-1 (SIRT1) was upregulated in CRC cells in response to glucose deprivation and oxidative stress. SIRT1 was also a hub of metabolic glucolipid conversion. SIRT1 upregulation deacetylated β-catenin, translocated it from the nucleus to the cytoplasm, attenuated glycolysis, and was positively correlated with fatty acid oxidation (FAO). Clinical analysis of SIRT1 expression in tumor tissues showed the SIRT1High profile was associated with poor prognosis in CRC patients. SIRT1 interference therapy significantly suppressed tumors in the mouse xenograft model.
Conclusions: In hostile, glucose-deficient TMEs, SIRT1 is upregulated, and CRC cells transform the Warburg phenotype to FAO. SIRT1 indicates the frequency of glucolipid transformation and rapid tumor progression and is a promising therapeutic target of CRC.
Keywords: β-catenin, colorectal cancer, metabolic glucolipid reprogramming, sirtuin-1, tumor development.