Clusterin gene is predominantly regulated by histone modifications in human colon cancer and ectopic expression of the nuclear isoform induces cell death.

Abstract

Clusterin (CLU) is an important glycoprotein involved in various cellular functions. Different reports have mentioned that the two isoforms of CLU; secretary (sCLU) and nuclear (nCLU) have opposite (paradoxical) roles in cancer development. sCLU provides pro-survival signal, whereas nCLU is involved in pro-apoptotic signaling. However, the molecular mechanism of CLU gene regulation is not clear as of yet. We hypothesize that CLU gene is regulated by DNA methylation and histone modifications and clusterin plays an important role in colon cancer. To evaluate the hypothesis, we investigated CLU expression in colon cancer tissues and DNA methylation and histone modification status of CLU gene promoter. It is apparent from immonohistology data that both benign and cancerous (primary and metastasis) formalin fixed paraffin embedded (FFPE) tissue samples exhibit CLU expression. However and interestingly only noncancerous tissue samples show nCLU expression. Ectopic expression of nCLU either by epigenetic modulators or by nCLU transfection is responsible for colon cancer cell death. To clarify the molecular mechanisms for regulation of expression of CLU isoforms, we have analyzed DNA methylation and histone modifications, such as histone H3K9me3, H3K27me3, H3K4me3, and H3K9AcS10P patterns around the CLU promoter. There is no remarkable change in the DNA methylation status upon treatment of the cells by AZA, TSA and SAM. Our findings clearly show that promoter histone H3K9me3 and H3K27me3 marks are elevated in comparison to H3K4me3 and H3K9AcS10P marks in colon cancer cell lines.

• Authors: Moonmoon Deb, Dipta Sengupta, Sandip Kumar Rath, Swayamsiddha Kar, Sabnam Parbin, Arunima Shilpi, Nibedita Pradhan, Sujit Kumar Bhutia, Subhendu Roy, Samir Kumar Patra
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1852 Issue 8 Pg. 1630-45 (Aug 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25917404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• CLU protein, human
• Clusterin
• Histones
• Protein Isoforms

Topics

• Adult
• Aged
• Base Sequence
• Cell Death (genetics)
• Cell Nucleus (genetics, metabolism)
• Clusterin (genetics, metabolism)
• Colonic Neoplasms (genetics, metabolism, pathology)
• DNA Methylation
• Gene Expression Regulation, Neoplastic
• Histones (metabolism)
• Humans
• Middle Aged
• Molecular Sequence Data
• Protein Isoforms (genetics, metabolism)
• Protein Processing, Post-Translational (physiology)
• Tumor Cells, Cultured