Chromatin Alterations in Tumorigenesis
Cancer cells show global changes in chromatin structure (DNA methylation and histone post-translational modifications), that lead to stable alterations in gene expression and potentially other nuclear functions (such as DNA replication and repair). Unlike genetic lesions, those alterations are reversible since the underlying DNA sequence is unchanged: this fundamental difference between genetic and epigenetic alterations makes the epigenome much more amenable to the development of therapeutic strategies. Indeed, small molecules with the capacity to interfere with chromatin modifying enzymes have antitumor activity. The concept of epigenetic therapy has been clinically validated with the approval by regulatory authorities of a small number of drugs for use in selected forms of cancer. In our view, however, drugs interfering with epigenetic enzymes (such as DNA methyltransferases and histone deacetylases, the most advanced targets in the epigenetic arena) have been used in the vast majority of cases rather aspecifically, without taking into account the context of chromatin alterations occurring in cancer cells. We surmise therefore that one of the major goals of both basic and applied research in this area should be the search of a set of epigenetic alterations in tumor cells, that dictate sensitivity or resistance to epigenetic drugs. More recently, we have started to address also the intersection between the epigenome and tumor cell metabolism, since several metabolites control the activity of chromatin modifying enzymes.
Most Relevant Publications
Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating PP2A-GSK3β-MCL-1 axis.
Cancer Cell, 2019
Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ER metastatic breast cancer.
Nat Genet, 2017
J Clin Invest, 2017