Page 45 - Hormel Report 2021

Role of hairless in skin homeostasis, stem cell maintenance, immune regulation, and UV-induced skin carcinogenesis.
The hairless gene encodes a transcription co-regu- lator that is essential for skin homeostasis and hair follicle cycling. Several lines of evidence suggest that hairless functions as a master regulator of skin homeostasis via controlling the expression of its target genes involved in cell proliferation, apoptosis, stem cell function and immune response. We recent- ly reported that hairless is an epigenetic regulator with histone demethylase activity. Mutational inacti- vation of hairless alone can dramatically increase tumor incidence and burden in response to chemical induction or UV radiation. In human skin squamous
cell carcinomas (SCCs) and other caner types, we found frequent deletions of the hairless gene. More- over, hairless expression is frequently down-regulat- ed in human SCCs but not benign actinic keratosis lesions. Through ChIP-seq studies, we have identified several hairless target genes that play important roles in cancer development. These findings clearly suggest that hairless is a pivotal tumor suppressor gene and prompted us to further define the anti- tumor activity of hairless, its target genes, and the role of histone methylation in regulating epidermal homeostasis, stem cell activity, and skin immunity. We are performing studies to elucidate the mech- anism by which hairless regulates immune gene activity and to probe the role of IL-36 signaling in skin inflammation and tumorigenesis. Ultimately, we hope to elucidate the genetic and epigenetic pathways through which hairless regulates skin homeostasis and to identify new hairless target genes that modu- late skin inflammation and cancer development.
Role of hairless mutation in breast cancer development.
The initiation and progression of breast cancer (BC), traditionally seen as a genetic disease, is now real- ized to involve epigenetic abnormalities along with genetic defects. Research over the past two decades has demonstrated that BC is an extremely hetero- geneous disease, comprising many subtypes that involve distinctive molecular pathogenesis. This heterogeneity underscores the importance of a comprehensive understanding of the genetic and epigenetic defects associated with BC biologic heterogeneity, in order to develop individualized
and targeted therapies to attack the specific mechanism(s) underpinning specific cancer sub- types. We have compelling evidence that hairless functions as a tumor suppressor gene during skin cancer development. Analysis of the human cancer genomics database reveals that genetic mutations
of hairless occur at a high frequency in patients
who suffer from aggressive BC subtypes. Moreover, analyzing the Cancer Cell Line Encyclopedia muta- tion database found that 17 out of 59 human BC cell lines harbor hairless gene copy number loss. Most of these hairless-deficient BC cell lines are also derived from aggressive BC subtypes, suggesting an intrigu- ing role of hairless in the development of aggressive BCs. However, its mechanism of action is unclear. In light of its novel function as an epigenetic regulator with histone demethylase activity, we are investigat- ing the function and mechanism of hairless in BC pathogenesis. The overarching goal of this project
is to define the anticancer function of hairless in BC development and to identify the genetic/epigenetic pathways through which hairless exerts its tumor suppressor function. We will also the efficacy of specific epigenetic drugs in inhibiting beast tumor growth and progression by targeting hairless- dependent epigenetic pathways in hairless-deficient breast tumors. If successful, such studies will enable clinical trials to test epigenetic drugs as new, effec- tive cancer therapies either alone or in combination with other cancer therapies.
| 45
Publications:
• Queen, D., Shen, Y., Lopez, A.T., Trager, M.H., Samie, F.H., Lewin, J.M., Niedt, G.W., Geskin, L.J., and Liu, L. (2020) UV signature genes for risk stratification of cutaneous actinic keratosis and squamous cell carcinoma subtypes. The FASEB Journal, 34:13022- 13032. PMID: 32776588.
• Trager, M.H., Sah, B., Chen, Z., and Liu, L. (2021) Control of Breast Cancer Pathogenesis by Histone Methylation and the Hairless Histone Demethylase. Endocrinology 162: 1-15. PMCID: PMC8237996.