Clinical and therapeutic significance of sirtuin-4 expression in colorectal cancer

Abstract

Several members of the sirtuin family (SIRT1-7), which are a highly conserved family of NAD+-dependent enzymes, play an important role in tumor formation. Recent studies indicate that SIRT4 acts as a tumor suppressor by regulating glutamine metabolism. In the present study, we investigated the expression and activity of SIRT4 in colorectal cancer. Using a tissue microarray of 89 colorectal cancer cases, we found that SIRT4 was significantly downregulated in colorectal cancer tissues compared with that noted in the corresponding normal tissue (P<0.001). Lower SIRT4 levels were associated with worse pathological differentiation (P=0.031) and poorer post-operative overall survival rate (P=0.041). We found that SIRT4 overexpression inhibited the proliferation of colorectal cancer cells in vitro and in vivo. SIRT4 inhibited the glutamine metabolism of colorectal cancer cells and synergistically with glycolysis inhibitors induced cell death. SIRT4 also increased the sensitivity of colorectal cancer cells to chemotherapeutic drug 5-fluorouracil by inhibiting the cell cycle. Together, these results highlight the prognostic value of SIRT4 in colorectal cancer and the potential application of SIRT4 in colorectal cancer treatment.

Who watches the watchmen? Regulation of the expression and activity of sirtuins

“…In accordance with a tumor-suppressive function of SIRT4, its mRNA level has been shown to be reduced in some human cancers (183)(184)(185). Furthermore, SIRT4knockout mice develop lung tumors at much higher incidence than wild-type littermates (186).…”

Sirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer

“…In previous studies, it has been shown that overexpression of SIRT4 in vitro inhibited the proliferation of HeLa and Myc -driven human Burkitt lymphoma cells by inhibiting glutamine metabolism. 42 , 44 Moreover, SIRT4 can inhibit the proliferation of RKO, 45 HT29, SW480, HCT116, 46 DLD-1, H1299, A549, and DU145 cells. 43 , 47 Overexpression of SIRT4 inhibited the migration and invasion of SW480, HCT116, H1299, and A549 cells.…”

“… 43 , 48 In vivo studies in nude mice have shown that knockout of SIRT4 in mouse embryonic fibroblast cells forms larger tumors. 42 , 45 , 47 Moreover, SIRT4 knockout mice spontaneously develop lung cancer, liver cancer, breast cancer, and lymphomas. 42 In a Tsc2 −/− murine embryonic fibroblast xenograft model, overexpression of SIRT4 reduced cell proliferation and transformation and delayed tumor development.…”

“… 47 In addition, SIRT4 overexpression resulted in a significant decrease in RKO tumor size in nude mice. 45 The Cancer Genome Atlas microarray database analysis indicated that at the mRNA level, SIRT4 mRNA levels in human breast, bladder, gastric, colon, thyroid, and ovarian cancers were decreased when compared with normal tissues. 42 , 47 Moreover, RT-PCR analysis of mRNA extracted from human tissue demonstrated that SIRT4 mRNA levels in colon, 45 breast, 49 endometrial, 50 and esophageal cancers were reduced.…”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…SIRT4 acts as a tumor suppressor in liver cancer, breast cancer and colorectal cancer [144][145][146]. Sirt4 KO mice can be spontaneously infected with lung cancer, liver cancer, breast cancer, and lymphomas [56].…”