Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

Abstract

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1–7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs in situ, these SIRTs may represent novel drug targets.

Divergent roles of sirtuin 1 in human granulosa-lutein cells: similarities to human chorionic gonadotropin

“…Controversial results were reported on SIRT1's impact on GC viability from various species, which will be described below [51][52][53][55][56][57]. In a recent study aimed to reveal the effect of SIRT1 on hGLC viability, SRT2104 was incubated with intact primary hGLCs and SVOG cells or with SIRT1-silenced cells [51,53].…”

“…A number of in vitro studies also suggested that SIRT1 is involved in diverse ovarian functions including ovarian cell proliferation, apoptosis, folliculogenesis, oogenesis, and secretory activity [30,[47][48][49][50][51][52][53][54][55][56][57][58]. This review aims to provide state-of-the-art information on the expression and divergent roles of SIRT1 in GC function.…”

Profound Effects of Dexamethasone on the Immunological State, Synthesis and Secretion Capacity of Human Testicular Peritubular Cells

“…A total of 1.2 × 10 5 cells were cultured in a 6-well plate overnight, as previously described [34]. Transfection was achieved using predesigned 10 nmol/L GR-siRNA (GR, #sc-35505, Santa Cruz Biotechnology, Dallas, TX, USA) or non-template (NT) control siRNA (10 nmol/L) with Lipofectamine RNA iMAX reagent (#13778150; ThermoFisher Scientific, Waltham, MA, USA) diluted in OPTI-MEM (#31985047, Gibco, ThermoFisher Scientific, Waltham, MA, USA), as described in the manufacturer's instructions.…”

Post-Translational Modifications by Lipid Metabolites during the DNA Damage Response and Their Role in Cancer

“…Sirtuins induce the deacetylation of a range of protein substrates, including histones, but also mediate ADP ribosylation. Furthermore, overexpression of SIRT1, 2, 3, and 7 have been identified in many types of cancer [ 120 , 121 , 122 ]. For example, overexpression of SIRT1 is known to prevent apoptosis by regulating histone deacetylation, promoter methylation, and histone methylation and inhibiting the transcription of tumor suppressor genes.…”