CCAAT/Enhancer-binding Protein δ Mediates Tumor Necrosis Factor α-induced Aurora Kinase C Transcription and Promotes Genomic Instability

Sin-Rong Wu,Chien-Feng Li,Liang-Yi Hung,A-Mei Huang,Joseph T Tseng,Jen-Hui Tsou,Ju-Ming Wang

doi:10.1074/jbc.m111.270710

Abstract

Epidemiologic and clinical research indicates that chronic inflammation increases the risk of certain cancers, possibly through chromosomal instability. However, the mechanism of inflammation-dependent chromosomal instability associated with tumorigenesis is not well characterized. The transcription factor CCAAT/enhancer-binding protein δ (C/EBPδ, CEBPD) is induced by tumor necrosis factor α (TNFα) and expressed in chronically inflamed tissue. In this study, we show that TNFα promotes aneuploidy. Loss of CEBPD attenuated TNFα-induced aneuploidy, and CEBPD caused centromere abnormality. Additionally, TNFα-induced CEBPD expression augmented anchorage-independent growth. We found that TNFα induced expression of aurora kinase C (AURKC) through CEBPD, and that AURKC also causes aneuploidy. Furthermore, high CEBPD expression correlated with AURKC expression in inflamed cervical tissue specimens. These data provide insight into a novel function for CEBPD in inducing genomic instability through the activation of AURKC expression in response to inflammatory signals.

Highlights

Vation of oncogenes such as nuclear factor-␬B (NF-␬B) or signal transducers and activators of transcription (STATs) cannot fully explain why inflammation can kill tumor cells and yet promote tumor growth
We found that the TNF␣-induced Ͼ4N HeLa cell population was reduced when CEBPD expression was attenuated by two RNAi (Fig. 1B), suggesting that CEBPD plays a functional role in the TNF␣-induced genomic instability
We found that the insensitive induction of CEBPD upon TNF␣ treatment caused larger HeLa cell focus formation on soft agar (Fig. 1C, left panel), in agreement with the hypothesis that CEBPD acts as a tumor suppressor

Summary

Introduction

Vation of oncogenes such as NF-␬B or STATs cannot fully explain why inflammation can kill tumor cells and yet promote tumor growth. We found that the TNF␣-induced Ͼ4N HeLa cell population was reduced when CEBPD expression was attenuated by two RNAi (Fig. 1B), suggesting that CEBPD plays a functional role in the TNF␣-induced genomic instability. After culturing for several passages, GFP expression was lost more readily in wild-type Cebpd MEF cells upon long-term TNF␣ treatment (supplemental Fig. S2), which indicated the greater ability to induce genomic instability.

Results

Conclusion