Tissue-autonomous cancer resistance of the naked mole-rat epidermis is mediated by highly elevated expression of the tumor suppressor and DNA repair genes in keratinocytes

Summary: Abstract Body: Naked mole rats (NMRs, Heterocephalus glaber) are unique long-lived mammals that possess marked resistance to cancer and other age-related pathologies maintaining a sustained healthy life-span for over 30 years. Despite remarkable longevity, there is a lack of any reported skin cancer incidents in NMRs, including basal/squamous cell carcinoma and melanoma. We found that FACS-sorted keratinocytes from normal NMR epidermis show >2-fold and higher expression of 325 tumor suppressor genes including 55 genes regulating DNA repair (Atr, Brca1, Ddx11, Ercc1, Ercc2, Fanca, Fankd2, Mlh1, Mnat1, Neil2, Rad1, Xpc, Xrcc1, Xrcc2) compared to normal mouse epidermal keratinocytes. In chemical skin carcinogenesis (DMBA/TPA) protocol applied to NMRs and FVB mice, as well as in the NMR skin transplanted onto immunodeficient nude mice, NMR skin show remarkable resistance to DMBA/TPA and do not develop papillomas for up to 25 weeks after treatment. Whole exome sequencing revealed that 6.5 weeks after DMBA/TPA treatment NMR epidermis show only 2.6% increase of single nucleotide variants compared to 90.8% increase seen in the mouse epidermis. Robust elimination of DMBA-induced mutations in NMRs was accompanied by significant decrease of gamma-H2AX+ cells in the epidermis 6.5 weeks after DMBA/TPA treatment compared to mice. RNAseq analyses demonstrated that after DMBA/TPA treatment NMR epidermis show upregulation of 21 tumor suppressor genes encoding several components of the DNA repair machinery (Adprh, Cenps, Ddb2, H2AX, Mgmt), inhibitors of cell proliferation (Cdk2ap1, Phb, Rasl10a, Rprm) and decreased expression of 46 oncogenes including Ccnd1, Myc, Pim1, Rel. These data provide evidence that NMR skin possesses unique cancer resistance in a tissue-autonomous manner and serve as a platform for further analyses of the mechanisms regulating highly elevated expression of the tumor suppressor and DNA repair genes in the NMR keratinocytes. Iqra Fatima¹, Andrei Mardaryev², Elena Rozhkova¹, Andrey Sharov¹, Vladimir A. Botchkarev¹ 1. Dermatology, Boston University, Boston, MA, United States. 2. Center of Skin Sciences, University of Bradford, Bradford, England, United Kingdom. UV Biology/Injury and Non-melanoma Cancers