Silencing speckle-type POZ protein by promoter hypermethylation decreases cell apoptosis through upregulating Hedgehog signaling pathway in colorectal cancer.

Xiaofei Zhi,Lei Zhang,Lilin Ma,Jun Qin,Jinqiu Tao,Ran Tao

doi:10.1038/cddis.2016.435

Abstract

Epigenetic silencing of tumor suppressors contributes to the development and progression of colorectal cancer (CRC). We recently found that speckle-type POZ protein (SPOP) was significantly downregulated and the inactivation of SPOP promoted metastasis in CRC. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in CRC. Our results revealed that the core region of SPOP promoter was hypermethylated in CRC tissues and its methylation was correlated with poor survival. Transcription factor RXRA had a vital role in the regulation of SPOP gene. The data indicated that DNA methylation at −167 bp of the SPOP gene altered the binding affinity between transcription factor RXRA and SPOP promoter. Moreover, SPOP was found to associate with Gli2 and promoted its ubiquitination and degradation in CRC. Consequently, the expression level of Hh/Gli2 pathway-related apoptotic protein Bcl-2 was decreased and the function of resisting cell death was inhibited in CRC. It suggests that methylation status of SPOP promoter can be used as a novel epigenetic biomarker and a therapeutic target in CRC.

Highlights

Hypermethylation has been linked to specific steps in the adenoma–carcinoma sequence, and is found to have a vital role in the initiation and progression of CRC.[2]
To evaluate the impact of DNA methylation pattern on transcriptional regulation of speckle-type POZ protein (SPOP) gene, we first analyzed which specific region within the SPOP gene promoter is critical to the regulation of gene transcription
We revealed that the tumor suppressor gene SPOP was inactivated by DNA methylation of its promoter region

Summary

Introduction

Hypermethylation has been linked to specific steps in the adenoma–carcinoma sequence, and is found to have a vital role in the initiation and progression of CRC.[2]. Ubiquitin-dependent proteolysis has an important role in the regulation of a variety of cellular processes, including cell proliferation, differentiation and apoptosis.[17] Ubiquitin (Ub) is attached to target proteins by a cascade enzyme system consisting of Ub-activating enzyme (E1), conjugating enzyme (E2) and ligating enzyme (E3). In this process, E3 enzyme determines the substrate specificity. We suggested that demethylation of SPOP promoter region can be used as the novel epigenetic therapy for colorectal cancer

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Conclusion