1. SIRT4 is the molecular switch mediating cellular proliferation in colorectal cancer through GLS mediated activation of AKT/GSK3β/CyclinD1 pathway.
- Author
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Cui Y, Bai Y, Yang J, Yao Y, Zhang C, Liu C, Shi J, Li Q, Zhang J, Lu X, and Zhang Y
- Subjects
- Animals, Cell Movement, Cell Proliferation, Colectomy, Colon pathology, Colon surgery, Colorectal Neoplasms surgery, Cyclin D1 metabolism, Female, Gene Knockdown Techniques, Glycogen Synthase Kinase 3 beta metabolism, HCT116 Cells, HT29 Cells, Humans, Mice, Mitochondrial Proteins genetics, Neoplasm Invasiveness, Protein Interaction Mapping, Protein Interaction Maps, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, Sirtuins genetics, Tumor Suppressor Proteins genetics, Xenograft Model Antitumor Assays, Carcinogenesis pathology, Colorectal Neoplasms pathology, Glutaminase metabolism, Mitochondrial Proteins metabolism, Sirtuins metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Mitochondria-localized sirtuin 4 (SIRT4) is associated with malignant phenotypes in colorectal cancer (CRC). However, the molecular mechanisms that drive SIRT4-mediated carcinogenesis are unclear. Initially, we confirmed expression of SIRT4 in CRC through public database and in CRC patient tissues using quantitative real-time reverse transcription PCR. We established HCT116 colorectal cells that overexpressed SIRT4 and HT29 cells were transfected with plasmids bearing a small interfering RNA construct to silence SIRT4. Assays to determine the malignant phenotypes (proliferation, invasion and migration) were performed. Xenograft in vivo models were also constructed. A protein interactome network was built using differentially expressed proteins identified using the liquid chromatography/tandem mass spectrophotometry, the findings of which were confirmed using co-immunoprecipitation, western blotting and phenotype rescue experiments. Decreased SIRT4 expression was associated with malignant phenotypes in vitro and in vivo. The ribosomal biogenesis pathway was enriched in the interactome network. SIRT4 suppression activated glutaminase, thereby initiating AKT activation. Our research provided novel insights into the molecular mechanisms underlying CRC, and identified that SIRT4 exerts its antitumor activity in CRC possibly dependent on glutaminase to inhibit proliferation, migration and invasion via the AKT/GSK3β/CyclinD1 pathway., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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