p53 inhibits the upregulation of sirtuin 1 expression induced by c-Myc

Abstract

Abstract. Sirtuin 1 (Sirt1), a conserved NAD + dependent deacetylase, is a mediator of life span by calorie restriction. However, Sirt1 may paradoxically increase the risk of cancer. Accordingly, the expression level of Sirt1 is selectively elevated in numerous types of cancer cell; however, the mechanisms underlying the differential regulation remain largely unknown. The present study demonstrated that oncoprotein c-Myc was a direct regulator of Sirt1, which accounts for the upregulation of Sirt1 expression only in the cells without functional p53. In p53 deficient cells, the overexpression of c-Myc increased Sirt1 mRNA and protein expression levels as well as its promoter activity, whereas the inhibitor of c-Myc, 10058-F4, induced decreased Sirt1 basal mRNA and protein expression levels. Deletion/mutation mapping analyses revealed that c-Myc bound to the conserved E-box[-189 to -183 base pair (bp)] of the Sirt1 promoter. In addition, p53 and c-Myc shared at least response element and the presence of p53 may block the binding of c-Myc to the Sirt1 promoter, thus inhibit the c-Myc mediated upregulation of Sirt1 promoter activity. The present study indicated that the expression level of Sirt1 was tightly regulated by oncoprotein c-Myc and tumor suppressor p53, which aids an improved understanding of its expression regulation and tumor promoter role in certain conditions. IntroductionSirtuin 1 (Sirt1), a conserved NAD + dependent deacetylase, has been implicated in modulating transcriptional silencing and cell survival, and is known to serve a role in tumorigene sis via deacetylation of important transcriptional factors, including tumor protein p53 (p53) (1), E2F transcription factor 1 (E2F1) (2) and nuclear factor-κB (3).Despite the paradoxical role of Sirt1 in tumorigenesis, the expression level of Sirt1 is increased in numerous types of cancer cell. Upregulation of Sirt1 is frequently observed in non-melanoma skin cancers, including actinic keratosis, Bowen's disease, squamous cell carcinoma and basal cell carcinoma (4). Sirt1 expression level is also significantly increased in poorly differentiated mouse and human prostate cancer (5), acute myeloid leukemia (AML) (6) and lymphoma (7).The expression level of Sirt1 is differentially regulated by oncogenes and tumor suppressor genes. p53 has been reported to repress the expression of Sirt1 and its removal by forkhead box O3 activated Sirt1 transcription in PC12 neuronal cancer cells (8,9). This model is further supported by studies investigating transformation-associated p53 knockout mice, which expressed constitutively higher Sirt1 mRNA expression levels in numerous tissues (10).Of note, hypermethylated in cancer 1 (HIC1), another tumor suppressor that acts as a repressor of Sirt1 expression level, formed a transcriptional repression complex with Sirt1, which induced inhibition of Sirt1 transcription (11). Sirt1 expression is regulated by the transcriptional factor E2F1, which binds two sites within the Sirt1 promoter. E2F1 is a crucial activator of Sirt1 expres...

<p>A New Regulatory Mechanism Between P53 And YAP Crosstalk By SIRT1 Mediated Deacetylation To Regulate Cell Cycle And Apoptosis In A549 Cell Lines</p>

“…It is well known that, P300 and CBP are the major acetylases for YAP and SIRT1 is its major deacetylase. More importantly, previous work has shown that, P53 inhibited SIRT1 activation by suppressing the pro-proliferation effector MYC,26 and SIRT1 regulates YAP-mediated cell proliferation and chemoresistance in hepatocellular carcinoma 20. Therefore, we hypothesized that SIRT1 is also required for the promoting effect of P53 on YAP acetylation.…”

Effects of SIRT1 silencing on viability, invasion and metastasis of human glioma cell lines

“…SIRT1 inhibition can suppress tumor growth ( 38 ). In addition, the tumor suppressor p53 downregulates SIRT1 expression in glioma tumor cells ( 39 ). SIRT1 also induces p53 inactivation and inhibits p53-dependent apoptosis ( 7 ).…”

TOPK inhibition accelerates oxidative stress‑induced granulosa cell apoptosis via the p53/SIRT1 axis

“…It has been suggested that p53 negatively regulates SIRT1 expression. It has also been suggested that p53 negatively regulates SIRT1 expression (11). The present study thus examined the effect of TOPK inhibition on the SIRT1 or p53 transcriptional level, and the effect of p53 expression on the SIRT1 transcriptional level upon H 2 O 2 stimulation.…”

“…It has been shown that various microRNAs (miRNAs or miRs) such as miRNA-590-3P or miRNA-494 suppress SIRT1 activity to promote apoptosis (7,8). It has been suggested that SIRT1 deacetylates lysine 382 of p53, thereby reducing p53 transcriptional activity and p53-mediated apoptosis, whereas p53 expression suppresses the transcription of SIRT1 gene induced by c-Myc (9)(10)(11).…”