Cistromics of hormone-dependent cancer
- 1Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA
2Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
3Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
- (Correspondence should be addressed to M Brown; Email: myles_brown{at}dfci.harvard.edu)
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Figure 1
Lineage- and stimuli-specific transcriptional programs are dependent on differential recruitment of ERα. Thousands of putative ERα-binding sites are found across the human genome. This includes over 60 000 estrogen-responsive elements (EREs) and a number of regions recruiting ERα through a tethering mechanism. However, lineage-specific ERα recruitment, as reported between breast and osteosarcoma cancer cell lines, is central to the unique transcriptional program generated in each cell type following estrogen (E2) treatment. Similarly, the transcriptional program activated through the PI3K/AKT pathway in MCF7 cells expressing a constitutively active AKT (CA-AKT) is dependent on a unique ERα recruitment pattern.
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Figure 2
Chromatin architecture reprogramming in castration-resistant prostate cancer cells. Similar to ERα in breast cancer cell lines, AR is recruited to a fraction of its putative binding sites in androgen-dependent prostate cancer cells. In castration-resistant prostate cancer cells, the genome-wide AR recruitment pattern is altered. This is dependent on the reprogramming of the chromatin architecture typified by de novo methylation of lysine 4 on histone H3 (H3K4me).
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Figure 3
Lineage-specific distribution of histone H3 methylation on lysine 4 guides FoxA1 recruitment. Differentiated cells are characterized by a unique distribution of epigenetic marks. FoxA1 will specifically be recruited to genomic regions harboring the forkhead motif (FKH) marked by H3K4me1/me2. Through its chromatin-remodeling activity, neighboring chromatin will be further opened and accessible to other transcription factors such as ERα and AR in breast and prostate cancer cells respectively. By contrast, FKH regions lacking H3K4me1/me2 will typically associate with H3K9me2 and be deprived of FoxA1 recruitment. Hence, the lineage-specific distribution of H3K4me1/me2 and H3K9me2 guides FoxA1 binding, which in turn restricts the recruitment of other transcription factors.
- © 2009 Society for Endocrinology
