Overexpression of SIRT4 inhibits the proliferation of gastric cancer cells through cell cycle arrest

Abstract

The sirtuins (SIRTs) are a family of nicotinamide-adenine dinucleotide (NAD)+-dependent protein deacetylases. SIRT4 is a mitochondrial NAD+-dependent adenosine diphsophate-ribosyltransferase. Recent studies demonstrated that SIRT4 can regulate glutamine metabolism and thus act as a tumor suppressor. However, the association of SIRT4 with gastric cancer remains unknown. The present study investigated the potential role of SIRT4 in the proliferation of human gastric cancer cells. Gastric cancer cell lines (SGC-7901 and MNK45) overexpressing SIRT4 were established by lentiviral infection. The effect of overexpression of SIRT4 in gastric cancer was evaluated by determining the cell viability, proliferation activity and colony-forming ability of gastric cancer cells in vitro. Furthermore, the cell cycle profiles of SGC-7901 and MNK45 cells overexpressing SIRT4 were evaluated to provide insights into potential underlying molecular mechanisms. Overexpression of SIRT4 significantly inhibited the proliferation and colony-forming ability of the gastric cancer cells in vitro. Furthermore, overexpression of SIRT4 induced G1 cell cycle arrest via suppression of phosphorylated extracellular signal-regulated kinase, cyclin D and cyclin E. In conclusion, the results of the present study indicated that SIRT4 may function as a tumor suppressor in gastric cancer by regulating cell proliferation, therefore SIRT4 may be a potential therapeutic target against this disease.

Research Progress of Sirtuin4 in Cancer

“…Researchers have shown that SIRT4 overexpression induced arrest of the G1 phase of the cell cycle by inhibiting expression of phosphorylated extracellular signal-regulated kinase (p-ERK), cyclin D and cyclin E ( 75 ). FCM and staining (propidium iodide) revealed that SIRT4 overexpression prominently increased the proportion of cells in the G1 phase and decreased the number of cells in the S phase of the cell cycle.…”

“…SIRT4 inhibited expression of cyclin D and cyclin E prominently. In addition, SIRT4 predominantly decreased p-ERK expression, but did not affect ERK expression ( 75 ). It has been reported that ERK controls the G1 phase of the cell cycle by regulating expression of cyclin D ( 76 ).…”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…There are reports that SIRT4 functions as a tumor suppressor, restraining the growth and proliferation of cells [56,[92][93][94]. SIRT4 can induce G1 cell cycle arrest by inhibiting phosphorylated extracellular signal-regulated kinase, cyclin D and cyclin E in gastric cancer [92]. Moreover, SIRT4 suppresses the malignant progression of non-small cell lung cancer (NSCLC) via ERK-Drp1 pathway-mediated mitochondrial dynamics [57].…”

Functions of mammalian SIRT4 in cellular metabolism and research progress in human cancer (Review)

“…This regulatory effect of SIRT4 was modulated by C-terminal binding protein and varied with glucose metabolic levels ( 98 , 99 ). Furthermore, overexpression of SIRT4 blocks cell cycle progression and decreases cancer cell replication by inactivating ERK, p-ERK, cyclin D, and cyclin E in thyroid cancer and gastric cancer cells ( 87 , 94 ).…”