Decreased sirtuin 4 expression is associated with poor prognosis in patients with invasive breast cancer

Shi,Qingyu; Liu,Tong; Zhang,Xianyu; Geng,Jingshu; He,Xiaohui; Nu,Ming; Pang,Da

doi:10.3892/ol.2016.5021

Decreased sirtuin 4 expression is associated with poor prognosis in patients with invasive breast cancer

Authors:
- Qingyu Shi
- Tong Liu
- Xianyu Zhang
- Jingshu Geng
- Xiaohui He
- Ming Nu
- Da Pang
View Affiliations

Affiliations: Department of Breast Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150040, P.R. China, Department of Pathology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150040, P.R. China, Department of Medical Records, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150040, P.R. China
Published online on: August 16, 2016 https://doi.org/10.3892/ol.2016.5021
Pages: 2606-2612
Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Aberrant metabolism is a hallmark of human cancer. Glutamine metabolism has been identified as a central metabolic pathway in cancer and thus, targeting glutamine metabolism may exhibit therapeutic potential. Sirtuin 4 (SIRT4) is an important molecule that mediates the blockade of glutamine catabolism by inhibiting glutamate dehydrogenase. In the present study, SIRT4 protein expression levels were analyzed in 409 breast cancer tissues and 241 paired adjacent non‑cancerous tissues by immunohistochemical analysis and the correlation between SIRT4 expression and the clinicopathological features was evaluated. SIRT4 protein was markedly increased in the breast cancer cells compared with adjacent non‑tumor mammary cells and was correlated with estrogen receptor, progesterone receptor, nuclear‑associated antigen Ki-67 and tumor protein p53 status, as well as breast cancer subtypes. Furthermore, low SIRT4 expression was associated with poor overall survival in breast cancers patients, particularly in Luminal A patients. Univariate and multivariate analyses confirmed that increased SIRT4 expression was an independent predictive factor of good prognosis for breast cancer patients. In conclusion, SIRT4 expression represents a significant favorable prognostic factor for patients with invasive breast cancer.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Zeng H, Zhang S and He J: Annual report on status of cancer in China, 2011. Chin J Cancer Res. 27:2–12. 2015. View Article : Google Scholar : PubMed/NCBI
3	Bange J, Zwick E and Ullrich A: Molecular targets for breast cancer therapy and prevention. Nat Med. 7:548–552. 2001. View Article : Google Scholar : PubMed/NCBI
4	Kung HN, Marks JR and Chi JT: Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia. PLoS Genet. 7:e10022292011. View Article : Google Scholar : PubMed/NCBI
5	Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, et al: The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 153:840–854. 2013. View Article : Google Scholar : PubMed/NCBI
6	Fernandez-Marcos PJ and Serrano M: Sirt4: The glutamine gatekeeper. Cancer Cell. 23:427–428. 2013. View Article : Google Scholar : PubMed/NCBI
7	DeBerardinis RJ, Lum JJ, Hatzivassiliou G and Thompson CB: The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7:11–20. 2008. View Article : Google Scholar : PubMed/NCBI
8	Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, et al: SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 126:941–954. 2006. View Article : Google Scholar : PubMed/NCBI
9	Sebastián C, Satterstrom FK, Haigis MC and Mostoslavsky R: From sirtuin biology to human diseases: An update. J Biol Chem. 287:42444–42452. 2012. View Article : Google Scholar : PubMed/NCBI
10	Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, Li YH, Wang X, Laurent G, German NJ, et al: SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell. 23:450–463. 2013. View Article : Google Scholar : PubMed/NCBI
11	He W, Newman JC, Wang MZ, Ho L and Verdin E: Mitochondrial sirtuins: Regulators of protein acylation and metabolism. Trends Endocrinol Metab. 23:467–476. 2012. View Article : Google Scholar : PubMed/NCBI
12	Vassilopoulos A, Fritz K S, Petersen DR and Gius D: The human sirtuin family: Evolutionary divergences and functions. Hum Genomics. 5:485–496. 2011. View Article : Google Scholar : PubMed/NCBI
13	Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, et al: Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 101:736–750. 2009. View Article : Google Scholar : PubMed/NCBI
14	Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B and Senn HJ: Panel members: Strategies for subtypes - dealing with the diversity of breast cancer: Highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 22:1736–1747. 2011. View Article : Google Scholar : PubMed/NCBI
15	Shaoqiang C, Yue Z, Yang L, Hong Z, Lina Z, Da P and Qingyuan Z: Expression of HOXD3 correlates with shorter survival in patients with invasive breast cancer. Clin Exp Metastasis. 30:155–163. 2013. View Article : Google Scholar : PubMed/NCBI
16	Liu T, Zhang X, Shang M, Zhang Y, Xia B, Niu M, Liu Y and Pang D: Dysregulated expression of Slug, vimentin, and E-cadherin correlates with poor clinical outcome in patients with basal-like breast cancer. J Surg Oncol. 107:188–194. 2013. View Article : Google Scholar : PubMed/NCBI
17	Lombard DB, Tishkoff DX and Bao J: Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. Handb Exp Pharmacol. 206:163–188. 2011. View Article : Google Scholar : PubMed/NCBI
18	Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, et al: SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell. 50:686–698. 2013. View Article : Google Scholar : PubMed/NCBI
19	Houtkooper RH, Pirinen E and Auwerx J: Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 13:225–238. 2012.PubMed/NCBI
20	Nasrin N, Wu X, Fortier E, Feng Y, Bare' OC, Chen S, Ren X, Wu Z, Streeper RS and Bordone L: SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem. 285:31995–32002. 2010. View Article : Google Scholar : PubMed/NCBI
21	Budczies J, Brockmöller SF, Müller BM, Barupal DK, Richter-Ehrenstein C, Kleine-Tebbe A, Griffin JL, Orešič M, Dietel M, Denkert C and Fiehn O: Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: Alterations in glutamine and beta-alanine metabolism. J Proteomics. 94:279–288. 2013. View Article : Google Scholar : PubMed/NCBI
22	McGuirk S, Gravel SP, Deblois G, Papadopoli DJ, Faubert B, Wegner A, Hiller K, Avizonis D, Akavia UD, Jones RG, et al: PGC-1α supports glutamine metabolism in breast cancer. Cancer Metab. 1:222013. View Article : Google Scholar : PubMed/NCBI
23	Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, et al: Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 476:346–350. 2011. View Article : Google Scholar : PubMed/NCBI
24	Wise DR and Thompson CB: Glutamine addiction: A new therapeutic target in cancer. Trends Biochem Sci. 35:427–433. 2010. View Article : Google Scholar : PubMed/NCBI
25	Tennant DA, Durán RV and Gottlieb E: Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 10:267–277. 2010. View Article : Google Scholar : PubMed/NCBI
26	DeBerardinis RJ and Cheng T: Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 29:313–324. 2010. View Article : Google Scholar : PubMed/NCBI
27	Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, et al: Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA. 107:7461–7466. 2010. View Article : Google Scholar : PubMed/NCBI
28	Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM, et al: SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 17:41–52. 2010. View Article : Google Scholar : PubMed/NCBI
29	Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, et al: SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell. 19:416–428. 2011. View Article : Google Scholar : PubMed/NCBI
30	Kumar S and Lombard DB: Mitochondrial sirtuins and their relationships with metabolic disease and cancer. Antioxid Redox Signal. 22:1060–1077. 2015. View Article : Google Scholar : PubMed/NCBI