The potential role of the autoimmune regulator (Aire) in tumorigenesis

Autoimmune regulator (Aire) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for induction of immunological self-tolerance.

On the molecular level Aire doesn’t function as a classical transcription factor, as it does not bind specific DNA sequences, instead it primarily localizes to transcription start sites (TSS) and/or enhancer regions. Results from our lab demonstrate that Aire utilizes a rather unconventional mechanism for transcriptional activation, which involves activation of the DNA damage response (Chuprin et al; submitted). Specifically, Aire induces formation of DNA damage foci in mTECs, characterized by phosphorylation of histone H2AX (e.g. gH2AX), and physically localizes to these DNA damage foci. Given that DNA damage is one of the key mediators of tumorigenesis, and that previous studies showed that Aire is also expressed in several types of human cancers such as skin tumor keratinocytes (Hobbs et al; Nature Genetic. 2015), breast cancer (Bianchi et al; Cell Cycle. 2016) and osteosarcoma (Matsuda et al; Clinical & Experimental Metastasis. 2018), the above data raise a question whether Aire may possess oncogenic activity.

To test this hypothesis, we generated a transgenic mouse model with inducible and ubiquitous expression of Aire and a mutation (R172H) in the main tumor suppressor gene - p53. These transgenic mice were injected once a month from age of 8 weeks either with sub-lethal dose of doxycycline (4ug/ml) to induce Aire expression or a control vehicle and followed for ~30 weeks. Interestingly while several mice with ectopic-Aire expression developed sarcoma tumors in the bladder and abdomen at 30 weeks, all mice with no ectopic expression of Aire were tumor free. As accumulating and non-resolved DNA damage is one of the key triggers for cancer development, these results suggests that Aire may possess potential oncogene activity and that ectopic expression of Aire in tissues other than the thymus may lead to cancer development.