Aberrant methylation and decreased expression of the TGF-β/Smad target gene FBXO32 in esophageal squamous cell carcinoma.

Abstract

BACKGROUND:

F-box protein 32 (FBXO32) (also known as atrogin-1), a member of the F-box protein family, has recently been identified as a transforming growth factor beta (TGF-β)/Smad target gene involved in regulating cell survival, and it may be transcriptionally silenced by epigenetic mechanisms in some kinds of carcinomas, yet its role in esophageal squamous cell carcinoma (ESCC) has not been defined.

METHODS:

The role of FBXO32 in ESCC and the correlation of FBXO32 methylation with a series of pathologic parameters were studied in a large cohort of patients with ESCC.

RESULTS:

Decreased messenger RNA (mRNA) expression and protein expression of FBXO32 were observed in esophageal cancer cell lines, and the silencing of FBXO32 could be reversed by treatment with 5-aza-2'-deoxycytidine or trichostatin A in the TE13 cell line. In addition, aberrant methylation of FBXO32 and histone deacetylation was capable of suppressing FBXO32 mRNA and protein expression in TE13 cells. Decreased mRNA and protein expression of FBXO32 was observed in ESCC tumor tissues and was associated with FBXO32 promoter methylation status. A positive correlation between FBXO32 and phosphorylated SMAD family members 2 and 3 expression and Smad4 protein expression also was observed in clinical specimens. FBXO32 methylation status and protein expression were independently associated with survival in patients with ESCC.

CONCLUSIONS:

FBXO32 may be a functional tumor suppressor. Its inactivation through promoter methylation could play an important role in ESCC carcinogenesis, and reactivation of the FBXO32 gene may have therapeutic potential and might be used as a prognostic marker for patients with ESCC.

• Authors: Wei Guo, Minghui Zhang, Supeng Shen, Yanli Guo, Gang Kuang, Zhibin Yang, Zhiming Dong
• Journal: Cancer (Cancer) Vol. 120 Issue 16 Pg. 2412-23 (Aug 15 2014) ISSN: 1097-0142 [Electronic] United States
• PMID: 24798237 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Cancer Society.

Chemical References

• Calmodulin-Binding Proteins
• Hydroxamic Acids
• Muscle Proteins
• RNA, Messenger
• Smad Proteins
• Transforming Growth Factor beta
• trichostatin A
• Decitabine
• FBXO32 protein, human
• SKP Cullin F-Box Protein Ligases
• Azacitidine

Topics

• Adult
• Aged
• Azacitidine (analogs & derivatives, pharmacology)
• Calmodulin-Binding Proteins (pharmacology)
• Carcinoma, Squamous Cell (genetics, metabolism)
• Cell Growth Processes (genetics)
• DNA Methylation
• Decitabine
• Esophageal Neoplasms (genetics, metabolism)
• Esophageal Squamous Cell Carcinoma
• Female
• Gene Silencing (drug effects)
• Humans
• Hydroxamic Acids (pharmacology)
• Immunohistochemistry
• Male
• Middle Aged
• Muscle Proteins (biosynthesis, genetics, metabolism)
• Promoter Regions, Genetic
• RNA, Messenger (biosynthesis, genetics)
• SKP Cullin F-Box Protein Ligases (biosynthesis, genetics, metabolism)
• Smad Proteins (biosynthesis, genetics, metabolism)
• Transforming Growth Factor beta (biosynthesis, genetics, metabolism)
• Up-Regulation (drug effects)