SIRT1 overexpression is an independent prognosticator for patients with esophageal squamous cell carcinoma

The standard therapy for patients with esophageal squamous cell carcinoma (ESCC) is surgery and concurrent chemoradiothrapy [1‐3]. Much improvement was achieved during the past decades. However, the tumor recurs despite of extensive surgery, and the prognosis was still unsatisfactory [1, 4, 5]. Identification of prognostic biomarkers for ESCC is crucial for clinicians to make risk-adapted treatment plans and the potential for novel target therapy.

Mammalian sirtuins deacetylases consist of seven family members (SIRT1–7) that have been shown to be critical regulators of cell signaling pathways [6, 7]. SIRT1 is a NAD + −dependent deacetylase that plays important roles in many biological processes, including stress response, apoptosis, cellular metabolism, adaptation to calorie restriction, aging, and tumorigenesis.

Because some members of the various classes of histone deacetylases (HDACs) have been shown to be overexpressed in diverse cancers, current views suggest that perturbed acetylation patterns on proteins may contribute to cellular transformation and tumor progression [6, 8, 9]. SIRT1 can activate stress defense and DNA repair mechanisms, and therefore aids in the preservation of genomic integrity [10, 11]. SIRT1 also functions in the regulation of metabolism and maintaining the integrity of the genome, and thus has been described as a potential tumor suppressor [11]. For example, both breast cancer and hepatocellular carcinoma exhibit reduced SIRT1 levels compared with normal tissues [12]. Wang et al. [12] demonstrated that Sirt1(+/−); p53(+/−) mice develop tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduces tumorigenesis, and thus suggested that SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity. Previous study [11] also showed that SIRT1 activity is required for suppressing survivin transcription, and reduction of survivin via SIRT1 activity may play an important role in breast cancer susceptibility gene 1 (BRCA1)-associated mammary tumor formation. Conversely, other studies showed that overexpression of SIRT1 caused the suppression of DNA damage repair proteins and factors involved in tumor suppression, and thus led to increased tumor growth and cell survival [11, 13]. Previous studies [11] revealed that SIRT1-mediated deacetylation suppresses the functions of several tumor suppressors, including p53, p73, and hypermethylated in cancer 1 (HIC1). Upregulation of SIRT1 has been reported in various human malignancies including prostate cancer, breast cancer, lung cancer, lymphoma, leukemia, soft tissue sarcomas, colon cancer, and gastric cancer [11, 14‐19]. In recent years, a number of inhibitors have been discovered and characterized. This raises the possibility that SIRT1 inhibition might suppress cancer cell proliferation [11]. However, the role of SIRT1 in ESCC remains largely undefined. Therefore, we conducted the present study to evaluate the prognostic significance of SIRT1 in patients with ESCC by immunohistochemistry and investigate the effect of SIRT1 inhibitor in vitro.

It is well known that advanced stage, higher histologic grade and residual disease after surgery lead to poor prognosis [1, 4, 5], and our study also showed the same result. In our study, we demonstrated that SIRT1 overexpression was an independent poor prognosticator for clinical outcome, and SIRT1 inhibitor suppressed cell proliferation of ESCC cell lines. Previous studies in several types of cancers [20‐38] also showed SIRT1 overexpression was correlated with advanced stages or poor prognosis and inhibition of SIRT1 may suppress tumor progression. There are several possible mechanisms involved in SIRT1 mediated tumor progression. First, Liu et al. [18, 20] reported that SIRT1 can maintain silent chromatin via the deacetylation of histone proteins, and thus protect cells from apoptosis. Second, SIRT1 can repress tumor suppressor genes, such as p53, p27^kip1, and FOXO family members, either by directly binding and deacetylating these non-histone proteins or by inducing heritable CpG island methylation at the gene promoter [18, 20, 30]. For example, previous studies [18, 20] showed that SIRT1 binds p53 and deacetylates its C-terminal Lys382, resulting in inhibition of p53 induction of cell cycle arrest and apoptosis in response to DNA damage and oxidative stress. Zhu et al. [30] reported that SIRT1 is an important regulator of p27^kip1 and SIRT inhibition induces senescence and antigrowth potential in lung cancer. Third, Byles et al. [27] also found that SIRT1 can enhance metastatic potential by inducing epithelial-mesenchymal transition in prostate cancer. Fourth, previous studies [29, 31] showed that SIRT1 is involved in chemotherapy resistance. Liang et al. [29] suggest that reduced glucose use and altered mitochondrial metabolism mediated by SIRT1 may contribute to cisplatin resistance. Taken together, the results from our study, together with previous findings, suggest that SIRT1 is not only an adverse prognosticator but also a potential novel therapeutic target.

Despite advance in perioperative management and surgical techniques, the prognosis of patients with ESCC remains poor [1, 2]. Even after radical surgery, patients still develop recurrences and metastases. Over the past decades, several post-operative adjuvant therapy clinical trials were performed to improve unsatisfactory cure rate achieved with surgery alone. Hence, identifying patients at high risk for recurrence who may benefit from post-operative adjuvant therapy is principal. In our study, overexpression of SIRT1 was highly representative of biological aggressiveness and independently associated with worse disease-free survival. The 5-year disease-free survival rate was only 26% in patients with SIRT1 overexpression, indicating that SIRT1 status may be used to select some patients for adjuvant therapy after esophagectomy.

Higher expression of SIRT1 is an independent prognosticator for patients with ESCC. The SIRT1 inhibitor suppressed cell proliferation of ESCC in vitro. Our findings suggest that Sirtuin inhibitors may be a potential therapy in ESCC patients with SIRT1 overexpression. There were two limitations in our study. First, the patient number was small and was retrospectively analyzed. Second, the effect of SIRT1 inhibitor was analyzed in cell line. The results need further studies to confirm our findings.