Daxx and TCF4 interaction links to oral squamous cell carcinoma growth by promoting cell cycle progression via induction of cyclin D1 expression.

Abstract

OBJECTIVES:

Death domain-associated protein (Daxx) has been recently implicated as a positive factor in ovarian cancer and prostate cancer, but the role of Daxx in oral squamous cell carcinoma (OSCC) has never been addressed. Herein, we investigate the expression and function of Daxx in OSCC.

MATERIALS AND METHODS:

RT-quantitative PCR, Western blotting, and immunohistochemistry were used to evaluation of the expression of Daxx in human OSCC cell lines and clinical surgical specimens. Short hairpin RNA targeting Daxx was transduced by lentivirus infection to knockdown the expression of Daxx in SAS and SCC25 cell lines, and the influence of this knockdown was evaluated by analyzing the growth and the cell cycle in transduced cells. Immunoprecipitation and sequential chromatin immunoprecipitation-quantitative PCR were used to analyze the associations between Daxx, TCF4, and cyclin D1 promoter. Xenograft tumor model was used to evaluate the in vivo tumorigenicity of Daxx in OSCC.

RESULTS:

Daxx mRNA and protein expression are elevated in several OSCC cell lines and human OSCC samples in comparison to those in normal tissue. We further find that depletion of Daxx decreases OSCC cell growth activity through G1 cell cycle arrest. Daxx silencing reduces cyclin D1 expression via a Daxx-TCF4 interaction, whereas the Daxx depletion-mediated G1 arrest can be relieved by ectopic expression of cyclin D1. Moreover, we show that in OSCC clinical samples, the expression of Daxx is significantly correlated with that of cyclin D1.

CONCLUSION:

Our data demonstrate the importance of Daxx in regulation of cyclin D1 expression and provide the first evidence that Daxx exhibits tumor-promoting activity in OSCC.

CLINICAL RELEVANCE:

Daxx plays an important role in malignant transformation of OSCC and may serves as a target for cancer prevention and treatment.

• Authors: Gu-Jiun Lin, Yen-Sung Huang, Chih-Kung Lin, Shing-Hwa Huang, Hsiu-Ming Shih, Huey-Kang Sytwu, Yuan-Wu Chen
• Journal: Clinical oral investigations (Clin Oral Investig) Vol. 20 Issue 3 Pg. 533-40 (Apr 2016) ISSN: 1436-3771 [Electronic] Germany
• PMID: 26205068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Co-Repressor Proteins
• DAXX protein, human
• Molecular Chaperones
• Nuclear Proteins
• TCF4 protein, human
• Transcription Factor 4
• Transcription Factors
• Cyclin D1

Topics

• Adaptor Proteins, Signal Transducing (physiology)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Blotting, Western
• Carcinoma, Squamous Cell (metabolism, pathology)
• Cell Cycle
• Cell Line, Tumor
• Co-Repressor Proteins
• Cyclin D1 (metabolism)
• Female
• Heterografts
• Humans
• Immunohistochemistry
• Male
• Mice
• Middle Aged
• Molecular Chaperones
• Mouth Neoplasms (metabolism, pathology)
• Nuclear Proteins (physiology)
• Real-Time Polymerase Chain Reaction
• Transcription Factor 4
• Transcription Factors (metabolism)