Taosheng Huang
Developmental & Cell Biology
School of Biological Sciences
Pediatrics, School of Medicine
Phone: (949) 824-9346
Email: huangts@uci.edu
http://www.ucihs.uci.edu/pediatrics/drhuang/
http://www.faculty.uci.edu/profile.cfm?faculty_id=5072
Taosheng Huang
One of Dr. Huang’s goals is to apply discoveries from rare genetic syndromes to understanding of common human diseases. Dr. Huang first studied the transcription factor TBX3 that is defective in the rare Ulnar-Mammary syndrome. Dr. Huang’s group showed that TBX3 is overexpressed in breast cancer cell lines and that two TBX3 isoforms have different functions in inhibition of senescence. The TBX3 isoforms are widely expressed in humans and mice, and the alternative splicing potentially is tissue and species specific. His group went on to show that overexpression of TBX3 can immortalize mouse embryo fibroblast cells, whereas the TBX3+2a isoform accelerates senescence. This functional difference could be explained by the fact that the two isoforms have different downstream targets. TBX3, but not TBX3+2a, binds to a previously identified T-box binding site in gel shift assays. These results show that the TBX3 isoforms have different roles in senescence and potentially play a role in breast cancer.
Recently, Dr. Huang’s group extended these results to human breast cancer tissues. Using immunohistochemistry, it was shown that TBX3 is overexpressed in malignant cells of primary breast cancer tissues. In addition, his group demonstrated that TBX3 interacts with the histone deacetylases (HDACs) 1, 2, 3 and 5 via two distinct binding sites. Deletion of the TBX3 repression domain (amino acids 566-624) completely abolishes its interaction with HDAC5. Interaction and co-localization of endogenous TBX3 and HDACs were shown in a breast cancer cell line by co-immunoprecipitation and immunofluorescence . TBX3 repress es expression of the p14 ARF tumor suppressor and that an HDAC inhibitor can reverse the TBX3 repressive function in a dosage-dependant manner. This suggests that TBX3 functions by recruiting HDACs to the T - box binding site in the promoter region and that TBX3 repression is dependent on HDAC activity. Thus TBX3 is a potential breast cancer biomarker with significant applications in both breast cancer diagnosis and treatment. In parallel, his group used a novel promoter array technique to identify promoters that directly bind to TBX3. Chromatin immunoprecipitation-guided ligation and selection (CHIP-GLAS) promoter array is a genome-wide assay that combines chromatin precipitation and microarray analysis, and it has the potential to identify 20,000 different promoter DNA/transcription factor interactions in one experiment. His group found TBX3 regulates more 400 genes, including known oncogenes and tumor suppressor genes, such as the Octamer-binding transcription factor-4 (OCT4 or POU5F1), the retinoic acid receptor ß (RARB), the single-stranded DNA binding protein 2 (SSBP2), the SKI-like oncogene (SKIL), and Gelsolin (GSN). OCT4 may play an important role in human embryo stem cell (huESC) differentiation as well as in breast cancer development.
Selected Publications:
Fan, W., Huang, X., Chen, C., Gray, J., and Huang, T. (2004). TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines. Cancer Res 64(15), 5132-9.
Yarosh, W., Barrientos, T., Esmailpour, T., Lin, L., Carpenter, P. M., Osann, K., Anton-Culver, H., and Huang, T. (2008). TBX3 is overexpressed in breast cancer and represses p14 ARF by interacting with histone deacetylases. Cancer Res 68(3), 693-9. |
