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Dynamic chromatin remodeling on the HER2 promoter in human breast cancer cells
S K Mishra1, M Mandal, A Mazumdar
1Department of Molecular and Cellular Oncology, Room Y4.6032, University of Texas M.D. Anderson Cancer Center-108, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Abstract:
Deregulation of the HER2 oncogene occurs in 30% of human breast cancers and correlates with poor prognosis and increased propensity for metastasis. Since the molecular basis of HER2 overexpression in human cancers is not known, we sought to determine whether chromatin remodeling pathways are involved in the regulation of HER2 expression. We report that compared with breast cancer cells expressing a low level of HER2, HER2-overexpressing breast cancer cells contained significantly higher levels of acetylated and phosphorylated histone H3, and acetylated histone H4 associated with the HER2 promoter. Decreased recruitment of histone deacetylases in the promoter is also noted in the HER2-overexpressing cell. The association of acetylated histone H4 with HER2 gene chromatin and HER2 expression in breast cancer cells was upregulated by an inhibitor of histone deacetylases. Treatment with histone deacetylase inhibitor also reduced the association of histone deacetylase-1 and -2 with the HER2 promoter. In addition, the tumor promoters 12-O-tetradecanoylphorbol-13-acetate and okadaic acid stimulated the association of phosphorylated histone H3 on serine 10 with the HER2 promoter and also stimulated HER2 expression. These findings identify histone acetylation and histone phosphorylation as novel regulatory modifications that target HER2 gene chromatin, and suggest that elevated levels of these chromatin-relaxing components in the vicinity of the HER2 gene promoter may constitute an important non-genomic mechanism of HER2 overexpression in human breast cancer.
Insights
Histone acetylation and phosphorylation, key chromatin remodeling processes, drive HER2 oncogene overexpression in breast cancer. This non-genomic mechanism contributes to poor prognosis and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- HER2 oncogene deregulation is observed in 30% of breast cancers, correlating with poor prognosis and metastasis.
- The molecular basis for HER2 overexpression remains largely unknown.
- Investigating chromatin remodeling pathways may elucidate HER2 gene regulation.
Purpose of the Study:
- To determine if chromatin remodeling pathways are involved in regulating HER2 expression.
- To identify specific histone modifications associated with HER2 overexpression.
- To explore the role of histone deacetylases (HDACs) in HER2 gene regulation.
Main Methods:
- Comparative analysis of histone modifications (acetylation, phosphorylation) at the HER2 promoter in HER2-low vs. HER2-overexpressing breast cancer cells.
- Assessment of histone deacetylase recruitment to the HER2 promoter.
- Treatment with a histone deacetylase inhibitor and tumor promoters (12-O-tetradecanoylphorbol-13-acetate, okadaic acid) to evaluate effects on HER2 expression and chromatin modifications.
Main Results:
- HER2-overexpressing cells exhibit increased acetylated/phosphorylated histone H3 and acetylated histone H4 at the HER2 promoter.
- Reduced histone deacetylase recruitment was observed at the HER2 promoter in overexpressing cells.
- Histone deacetylase inhibition upregulated acetylated histone H4 and HER2 expression, while decreasing HDAC-1/-2 association with the promoter.
- Tumor promoters increased phosphorylated histone H3 and HER2 expression.
Conclusions:
- Histone acetylation and phosphorylation are novel regulatory modifications targeting HER2 gene chromatin.
- Elevated chromatin-relaxing components at the HER2 promoter may represent a non-genomic mechanism for HER2 overexpression in breast cancer.
- These findings offer potential therapeutic targets for HER2-driven breast cancers.