MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells.

Abstract

BACKGROUND:

The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer.

METHODS:

Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors.

RESULTS:

The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice.

CONCLUSIONS:

These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition.

• Authors: Hasan Rajabi, Rehan Ahmad, Caining Jin, Maya Datt Joshi, Minakshi Guha, Maroof Alam, Surender Kharbanda, Donald Kufe
• Journal: The Prostate (Prostate) Vol. 72 Issue 15 Pg. 1659-68 (Nov 2012) ISSN: 1097-0045 [Electronic] United States
• PMID: 22473899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Androgens
• MIRN135 microRNA, human
• MUC1 protein, human
• MicroRNAs
• Mucin-1
• RNA, Messenger
• Receptors, Androgen

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Androgens (metabolism)
• Cell Proliferation
• Down-Regulation
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• MicroRNAs (metabolism)
• Molecular Targeted Therapy
• Mucin-1 (genetics, metabolism)
• Neoplasm Invasiveness
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Binding
• Protein Processing, Post-Translational
• RNA, Messenger (metabolism)
• Receptors, Androgen (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction