Gene expression is dynamically controlled by epigenetics through post-translational modifications of histones, chromatin-associated proteins and DNA itself. All these elements are required for the maintenance of chromatin structure and cell identity in the context of a normal cellular phenotype. Disruption of epigenetic regulation is a common event in human cancer. Here, we review the key protein families that control epigenetic signalling through writing, erasing or reading specific post-translational modifications. By exploiting the leading role of epigenetics in tumour development and the reversibility of epigenetic modifications, promising novel epigenetic-based therapies are being developed. In this article, we highlight the emerging low MW inhibitors targeting each class of chromatin-associated protein, their current use in preclinical and clinical trials and the likelihood of their being approved in the near future.
1609 Imbalance of the BRCA1 pathway is a major hallmark of human breast cancer. In this context, germline point mutation and CpG island promoter hypermethylation of BRCA1 are a feature of breast neoplasms. Inactivation by promoter hypermethylation of the BRCA1-binding protein SRBC could constitute another way by which this cellular network may be altered in human cancers. If both BRCA1 and SRBC act in the same pathway, simultaneous molecular lesions in the two genes in the same tumor should be a rare event. To test whether this inverse association exists, we have analyzed the BRCA1 and BRCA2 mutational and CpG island hypermethylation status versus SRBC CpG island hypermethylation of a large collection of sporadic and inherited breast tumors. No association was found between the methylation status of SRBC and the BRCA2 mutational status. However, our results demonstrate that the epigenetic alteration of SRBC is confined to breast tumors without BRCA1 hypermethylation or BRCA1 germline mutations. Thus, the mutual exclusivity of the epigenetic and genetic alterations in BRCA1 and SRBC suggests that both genes play a critical and cooperative role in human tumorigenesis.
