HDAC1 and HDAC2 as regulators of tumorigenesis

Histone deacetylases (HDACs) are chromatin-associated regulators ofcell cycle progression, proliferation and differentiation. The use of small molecule HDAC inhibitors is a promising approach for cancer therapy and pan-HDAC inhibitors have been FDA-approved for treatment of cutaneous T-cell lymphomas. However, the function of individual members of the HDAC family in cancer is largely unknown. The closely related class I deacetylases HDAC1 and HDAC2 are excellent candidates as targets for tumor therapy because they are highly expressed in proliferating and tumor cells and are known regulators of mammalian cell proliferation. We have recently identified HDAC1 and HDAC2 as regulators of epidermal proliferation in a transgenic mouse model (Winter et al. (2013), EMBO J.). HDAC1 and HDAC2 significantly contribute to the total cellular deacetylase activity in the epidermis and partial reduction of HDAC1/HDAC2 activity results in epidermal hyperproliferation and spontaneous tumor formation. Surprisingly, loss of HDAC1 but not HDAC2 in the genetically induced SOS skin tumor model leads to hyperproliferation and enhanced tumor formation. In contrast, complete loss of HDAC1/HDAC2 activity in the epidermis causes impaired cell proliferation and apoptosis. Based on these data we hypothesize that depending on the gene dosage and the affected isoforms HDAC1 and HDAC2 have either oncogenic or oncosuppressor functions in the epidermis. Non-melanoma skin cancer is the most frequent cancer in the world but relatively few deaths are caused by it. However, squamous cell carcinoma (SCC) such as head-and-neck SCC is responsible for a quarter of million deaths annually. In this project we will examine whether HDAC1 and HDAC2 together are potential targets for skin tumor and SCC therapy. We will combine mouse genetics, shRNA-mediated knockdown approaches, application of novel inhibitors and genome-wide expression analyses to define the roles of HDAC1 and HDAC2 in murine and human cancer. We will compare the consequences of genetic ablation of Hdac1/Hdac2 with pharmacological inactivation of HDAC1/HDAC2 by isoform-specific inhibitors both in mouse and human skin tumors and will test a potential chemosensitizing effect of HDAC1/HDAC2-specific inhibitors. Our project will provide insights into the individual and redundant functions of HDAC1 and HDAC2 in the regulation of epidermal tumor development and maintenance and will be highly relevant for the application of HDAC inhibitors as anti-tumor therapeutics.

As the outermost organ of the body the skin is continuously exposed to pathogens and plays a critical role in defense against the environment and infectious agents. The most superficial layer of the skin, the epidermis, functions as a critical barrier against viruses, bacteria and fungi. Epigenetic mechanisms are crucial for the protective function of the epidermis. The innate human immune system is capable of recognizing and fighting pathogens such as viruses, bacteria or parasites. In addition to other conserved structure, it can detect pathogens based on their RNA and DNA. Since these nucleic acids are also present in human cells the immune system must be able to differentiate endogenous substances from exogenous ones in order to avoid autoinflammation or autoimmune diseases. This mechanism is also known as self/non-self discrimination. In this project we show that the epigenetic key enzyme DNA methyltransferase 1 is an important factor in preventing autoinflammation. Methylation of DNA is one of the most important epigenetic mechanisms in our cells. It not only controls cell-specific gene expression but prevents the activation of endogenous viruses, the so-called transposons, which can change their position within the genome and may induce cellular defence mechanisms. Loss of the key epigenetic enzyme DNA methyltransferase 1 results in autoinflammation and pathological changes occur in the skin. Reduced DNA methylation results in genomic instability, leading to the formation of cytoplasmic DNA. When these micronuclei are formed, cGAS, one of the main regulators of the innate immune system, erroneously recognizes the DNA as foreign or "non-self" and activates the immune system. These findings are particularly relevant for further investigations to understand the molecular mechanisms of autoinflammatory diseases but may also provide an explanation for the positive effects of epigenetic drugs on the efficacy of immunotherapy against cancer.