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Histone deacetylases (HDACs) induce gene repression and modify the activity of nonhistone proteins. In a new article in the Journal of Investigative Dermatology, Zhu et al. (2021) demonstrate essential roles for HDAC1/2 in maintaining keratinocyte proliferation and survival in adult epidermis and basal cell carcinoma, thus providing a rationale for using HDAC inhibitors for the treatment of hyperproliferative and neoplastic skin disorders.
In normal adult epidermis, HDAC1/2 promote cell proliferation via deacetylation of p53 protein and suppress senescence via repression of the p16Ink4A gene.
HDAC1/2 maintain proliferation and inhibit apoptosis in pre–basal cell carcinoma (BCC) lesions by inhibiting both p53 and p16 activity.
Pharmacological inhibition of HDAC1/2 activity decreases keratinocyte proliferation and diminishes epidermal thickening/invagination in pre-BCCs, suggesting an opportunity for using HDAC inhibitors for BCC treatment.
Signaling/transcription factor–mediated and epigenetic regulatory mechanisms operate in concert to control epidermal proliferation and differentiation. Transcription factors, including p63, regulate expression of the distinct components of the epigenetic machinery and interact with epigenetic regulators to control gene transcription and the activity of lineage-specific enhancers in keratinocytes (KCs) (
). In turn, epigenetic enzymes involved in regulating post-translational covalent histone modifications and gene transcription can also modify nonhistone substrates, including transcription factors, thus changing their activities (
Post-translational covalent modifications of histone molecules include lysine acetylation, which is regulated by histone acetyl transferases (HATs) and histone deacetylases (HDACs) exhibiting opposite functions (
HDACs form a multiprotein family, in which each member plays distinct yet partially overlapping roles in coordinating the interactions of signaling pathways with chromatin remodeling and transcription factor function to modulate gene expression (
). HDAC1 and HDAC2 exhibit significant functional redundancy, and genetic ablation of both enzymes or inhibition of their activities via small molecules results in reduction of cell proliferation in many organs and cell lineages (
). Because HDACs regulate cell proliferation, HDAC inhibitors have been tested as promising drugs for cancer therapy and received Food and Drug Administration approval for the treatment of cutaneous T-cell lymphoma (
To better understand the role of HDAC1/2 in the control of epidermal proliferation and differentiation during development, the Millar lab used genetically engineered mice with Krt14-Cre–mediated conditional deletion of genes encoding both enzymes in the epidermis and demonstrated that Hdac1/2-null skin epithelia failed to differentiate and remained single-layered, similar to that in p63-null mice (
). Gene expression program analysis in HDAC1/2-deficient skin epithelium indicated that expression of the p63 gene and its positive gene targets were not affected, whereas selected cell cycle inhibitor genes normally repressed by ΔNp63, including Cdkn1a/p21 and p16Ink4A, were upregulated in the absence of HDAC1/2 activity (
In addition to coregulation of the p63-repressed genes, HDAC1/2 exhibited effects on nonhistone target proteins and deacetylated either lysine 379 or lysine 386 of the p53 molecule, thus suppressing its ability to induce apoptosis and activate the cyclin-dependent kinase inhibitor gene Cdkn1a/p21 in KCs (
), the Millar lab demonstrated that Hdac1/2cKO mice that were also null for p53 had partially restored epidermal proliferation, indicating that the effects of HDAC1/2 deletion on KC proliferation are mediated in part via increased p53 activity. Furthermore, following deletion of p16Ink4A from Hdac1/2cKO mice,
). The authors demonstrate that HDAC1/2 proteins are expressed in pre-BCC lesions, whereas the genetic ablation of Hdac1/2 reduced epidermal thickening and invagination, inhibited proliferation, and increased apoptosis in KCs of doxycycline-treated Krt5-rtTA tetO-GLI2ΔN tetO-Cre Hdac1fl/fl/Hdac2fl/fl mice (
). Concomitant loss of either p53 or p16 in the corresponding compound mouse models partially rescued the decreased cell proliferation and increased apoptosis caused by Hdac1/2 deletion in GLI2ΔN-expressing epidermis, suggesting that both p53 and p16 are required to maintain proliferation and inhibit apoptosis in pre-BCC lesions (
), on the development of doxycycline-induced pre-BCC lesions in Krt5-rtTA tetO-GLI2ΔN mice. The authors show that, consistent with the data obtained in genetically engineered mouse models, pharmacological inhibition of HDAC1/2 activity decreases KC proliferation and diminishes epidermal thickening and invagination in GLI2ΔN-induced pre-BCCs (
). However, the inhibitory effects of romidepsin on pre-BCC development and KC proliferation were significantly diminished by loss of the p16Ink4A gene, thus suggesting that p16 is an important target for HDAC1/2 regulation in neoplastic KCs.
provide an important platform for further analyses of canonical and noncanonical functions of HDACs in the control of epidermal homeostasis in normal and neoplastic skin (Figure 1). In particular, these data open a new avenue for analyses of the roles of distinct HDACs in controlling alterations in gene expression programs in KCs in epidermal differentiation disorders, such as psoriasis. These studies are also important in the context of the rapidly developing approaches for pharmacological modulation of HDAC activity. Indeed, numerous small molecules inhibiting HDAC activities, as well as the dual action compound inhibiting simultaneously HDACs and other component of the CoREST complex lysine specific demethylase LSD1, have been developed and need to be tested for efficacy in neoplastic and hyperproliferative skin conditions (
). Understanding HDAC-dependent mechanisms that control epidermal proliferation and differentiation and their alterations in different pathological skin conditions will facilitate development of novel approaches for treatment of skin disorders by targeting distinct HDAC proteins.
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.