Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK–JMJD3–p16INK4a signaling axis

Abstract

The B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and a downstream target of p53. BTG3 also binds and inhibits E2F1. Although it connects functionally two major growth-regulatory pathways, the physiological role of BTG3 remains largely uncharacterized. Here, we present evidence that loss of BTG3 in normal cells induced cellular senescence, which was correlated with enhanced ERK-AP1 signaling and elevated expression of the histone H3K27me3 demethylase JMJD3/KDM6B, leading to acute induction of p16(INK4a). Importantly, we also found that BTG3 expression is specifically downregulated in prostate cancer, thus providing a physiological link with human cancers. Our data suggest that BTG3 may have a fail-safe role against tumorigenic progression.

Down-regulation of BTG3 promotes cell proliferation, migration and invasion and predicts survival in gastric cancer

“…As follows, its physiological functions began to be discovered, such as neuron phylogenesis, the control of muscle cell development and bone formation (Putnik et al 2012), especially, for the control of cell cycle (Winkler 2010;Lim 2006;Yamamoto et al 2001;Lin et al 2012). Recently, several studies have shown that BTG3 was associated with tumorigenesis.…”

“…The expression of BTG3 is down-regulated in lung adenocarcinoma, oral squamous cell cancer or prostate cancer (Yoneda et al 2009;Yamamoto et al 2001;Lin et al 2012). Aberrant epigenetic regulation of BTG3 promoter, such as by DNA hypermethylation and/or histone modification, is observed in several human cancers (Majid et al 2009(Majid et al , 2010Yu et al 2008;Putnik et al 2012).…”

MiR-106b-5p Promotes Proliferation and Inhibits Apoptosis by Regulating BTG3 in Non-Small Cell Lung Cancer

“…Recent researches demonstrate that the family could inhibit cell proliferation and regulate cell-cycle progression and differentiation in a variety of cell types [26, 27]. At present, numerous studies have demonstrated that BTG3 plays a suppressive role in cancer progression and the down-expression of BTG3 could lead to the development of gastric cancer, lung cancer, esophageal adenocarcinoma, and prostate cancer [28-31]. All these results suggest that BTG3 might function as a tumor suppressor in many systems.…”

Direct Downregulation of B-Cell Translocation Gene 3 by microRNA-93 Is Required for Desensitizing Esophageal Cancer to Radiotherapy

“…Recent evidence has demonstrated that BTG3 functions as a tumor suppressor in cancer progression. BTG3 expression is downregulated in lung adenocarcinoma, oral squamous cell cancer, or prostate cancer [19][20][21][22]. It was reported that BTG3 was a suppressor in the ESC progression [4].…”