One of the PRC2 components, the catalytic protein EZH2, was previously shown to be highly expressed in the most aggressive types of cancer, very much in agreement with the observations that this protein fulfills a central role in carcinogenesis.
In collaboration with investigators from the National Institutes of Health and Novartis Institute for Biomedical Sciences, Kapil N. Bhalla, M.D., professor of medicine and director of the Medical College of Georgia Cancer Center, recently showed that the combined treatment with 3-Deazaneplanocin A, an S-adenosyl-L-homocysteine hydrolase inhibitor, and panobinostat, a pan-histone deacetylase inhibitor, caused more depletion of EZH2, and of trimethylated lysine 27 marks on histone H3, than either compound alone.
In addition, the two compounds synergistically increased apoptosis in cultured and primary acute myeloid leukemia cells, but not in normal bone marrow progenitor cells. “This opens up the very exciting possibility that perhaps combining histone deacetylase and methytransferase inhibitors represents a good therapeutic option to target epigenetic modifications in acute leukemia, and perhaps in lymphomas, too, because EZH2 was also implicated in some lymphomas,” predicts Dr. Bhalla.
In addition to the work on acetylation and methylation in the context of cancer epigenetics, another interest in Dr. Bhalla’s group focuses on the involvement of heat shock proteins (Hsp) as molecular chaperones in cancer. Cancer cell metabolism creates a considerable amount of stress, and one of the main categories, known as proteotoxic stress, is mediated by the misfolded or unfolded protein response. Heat shock proteins are essential in maintaining the correctly folded conformation and activity of oncoproteins, and thus allow cancer cells to survive the stress response.
A few years ago, Susan Lindquist, Ph.D., and collaborators from the Massachusetts Institute of Technology and Howard Hughes Medical Institute, showed that deletion of heat shock factor 1, the master eukaryotic heat shock regulator, protected mice from tumors induced by mutations in the RAS oncogene or the p53 tumor suppressor gene, indicating that heat shock proteins are essential for cancer development.
The use of molecular chaperones as therapeutic targets for malignant tumors emerges as an exciting idea, and several Hsp90 inhibitors are currently being investigated as potential anticancer agents.
In collaboration with Ari Melnick, M.D., from Cornell University, Dr. Bhalla recently showed that Hsp90 inhibitors selectively kill diffuse B-cell lymphomas by targeting the Bcl-6 transcriptional repressor, a common oncoprotein that represses several tumor suppressor genes. The therapeutic potential of Hsp90 inhibitors is especially valuable in context of the high toxicity of certain regimens currently used to treat lymphomas. “With Hsp90 inhibitor, the possibility to modulate the proteotoxic stress phenotype of cancer cells, used in combination with a targeted agent against the oncoprotein kinase, to which the cancer is addicted to, would constitute a very attractive therapeutic option,” says Dr. Bhalla.