Title: HDAC1/2 Control Proliferation and Survival in Adult Epidermis and Pre‒Basal Cell Carcinoma through p16 and p53.
Authors: Zhu, Xuming; Leboeuf, Matthew; Liu, Fang; Grachtchouk, Marina; Seykora, John T; Morrisey, Edward E; Dlugosz, Andrzej A; Millar, Sarah E
Published In J Invest Dermatol, (2022 Jan)
Abstract: HDAC inhibitors show therapeutic promise for skin malignancies; however, the roles of specific HDACs in adult epidermal homeostasis and in disease are poorly understood. We find that homozygous epidermal codeletion of Hdac1 and Hdac2 in adult mouse epidermis causes reduced basal cell proliferation, apoptosis, inappropriate differentiation, and eventual loss of Hdac1/2-null keratinocytes. Hdac1/2-deficient epidermis displays elevated acetylated p53 and increased expression of the senescence gene p16. Loss of p53 partially restores basal proliferation, whereas p16 deletion promotes long-term survival of Hdac1/2-null keratinocytes. In activated GLI2-driven pre-basal cell carcinoma, Hdac1/2 deletion dramatically reduces proliferation and increases apoptosis, and knockout of either p53 or p16 partially rescues both proliferation and basal cell viability. Topical application of the HDAC inhibitor romidepsin to the normal epidermis or to GLI2ΔN-driven lesions produces similar defects to those caused by genetic Hdac1/2 deletion, and these are partially rescued by loss of p16. These data reveal essential roles for HDAC1/2 in maintaining proliferation and survival of adult epidermal and basal cell carcinoma progenitors and suggest that the efficacy of therapeutic HDAC1/2 inhibition will depend in part on the mutational status of p53 and p16.
PubMed ID: 34284046
MeSH Terms: Animals; Antibiotics, Antineoplastic/pharmacology; Antibiotics, Antineoplastic/therapeutic use; Apoptosis; Carcinogenesis; Carcinoma, Basal Cell/drug therapy; Carcinoma, Basal Cell/genetics; Carcinoma, Basal Cell/metabolism*; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16/genetics; Cyclin-Dependent Kinase Inhibitor p16/metabolism*; Depsipeptides/pharmacology; Depsipeptides/therapeutic use; Epidermis/physiology*; Histone Deacetylase 1/antagonists & inhibitors; Histone Deacetylase 1/genetics; Histone Deacetylase 2/antagonists & inhibitors; Histone Deacetylase 2/genetics; Humans; Keratinocytes/physiology*; Mice; Mice, Inbred C57BL; Mice, Knockout; Precancerous Conditions; Skin Neoplasms/drug therapy; Skin Neoplasms/genetics; Skin Neoplasms/metabolism*; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism*