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Histone Deacetylases in the Control of Epidermal Homeostasis: From Chromatin Biology toward Therapy

Published:September 22, 2021DOI:https://doi.org/10.1016/j.jid.2021.06.021
      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) (
      • Adam R.C.
      • Fuchs E.
      The yin and yang of chromatin dynamics in stem cell fate selection.
      ;
      • Botchkarev V.A.
      • Flores E.R.
      p53/p63/p73 in the epidermis in health and disease.
      ;
      • Kang S.
      • Chovatiya G.
      • Tumbar T.
      Epigenetic control in skin development, homeostasis and injury repair.
      ;
      • Soares E.
      • Zhou H.
      Master regulatory role of p63 in epidermal development and disease.
      ). 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 (
      • Zhang X.
      • Huang Y.
      • Shi X.
      Emerging roles of lysine methylation on non-histone proteins.
      ).
      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 (
      • Kelly R.D.
      • Cowley S.M.
      The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts.
      ). Histone hyperacetylation catalyzed by HATs has been correlated with transcription activation, whereas HDAC-mediated histone hypoacetylation is usually correlated with gene repression (
      • Kelly R.D.
      • Cowley S.M.
      The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts.
      ).
      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 (
      • Kelly R.D.
      • Cowley S.M.
      The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts.
      ). 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 (
      • Kelly R.D.
      • Cowley S.M.
      The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts.
      ). 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 (
      • Ramaiah M.J.
      • Tangutur A.D.
      • Manyam R.R.
      Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy.
      ).
      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 (
      • LeBoeuf M.
      • Terrell A.
      • Trivedi S.
      • Sinha S.
      • Epstein J.A.
      • Olson E.N.
      • et al.
      Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells.
      ). 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 (
      • LeBoeuf M.
      • Terrell A.
      • Trivedi S.
      • Sinha S.
      • Epstein J.A.
      • Olson E.N.
      • et al.
      Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells.
      ).
      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 (
      • LeBoeuf M.
      • Terrell A.
      • Trivedi S.
      • Sinha S.
      • Epstein J.A.
      • Olson E.N.
      • et al.
      Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells.
      ). Thus, HDAC1/2 directly mediate the repressive activity of p63 in KCs via binding to promoters of the p63 target genes and independently suppress p53 activity via deacetylation of p53 protein (
      • LeBoeuf M.
      • Terrell A.
      • Trivedi S.
      • Sinha S.
      • Epstein J.A.
      • Olson E.N.
      • et al.
      Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells.
      ).
      In an important follow-up study performed on adult mouse epidermis and published in this article (
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      ), 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,
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      show that p16Ink4A deletion enables survival of Hdac1/2-deficient KCs by preventing their senescence, rather than by rescuing decreased cell proliferation or apoptosis.
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      conclude that in the normal adult epidermis, HDAC1/2 promote cell proliferation via deacetylation of p53 protein and suppress senescence via repression of p16Ink4A gene.
      HDACs regulate the expression and activity of numerous proteins involved in cancer initiation and progression in many organs (
      • Ramaiah M.J.
      • Tangutur A.D.
      • Manyam R.R.
      Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy.
      ). To address the roles of HDAC1/2 in the control of basal cell carcinoma (BCC) initiation,
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      utilized doxycycline-inducible expression of a constitutively active form of GLI2 in KCs using a previously established Krt5-rtTA tetO-GLI2ΔN mouse model (
      • Grachtchouk M.
      • Pero J.
      • Yang S.H.
      • Ermilov A.N.
      • Michael L.E.
      • Wang A.
      • et al.
      Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations.
      ). 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 (
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      ). 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 (
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      ).
      One of the intriguing findings uncovered by
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      is the demonstration of the effects of romidepsin, a class I HDAC inhibitor approved for treatment of cutaneous T-cell lymphoma (
      • Ramaiah M.J.
      • Tangutur A.D.
      • Manyam R.R.
      Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy.
      ), 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 (
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      ). 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.
      Taken together, the data of
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      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 (
      • Kalin J.H.
      • Wu M.
      • Gomez A.V.
      • Song Y.
      • Das J.
      • Hayward D.
      • et al.
      Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.
      ;
      • Ramaiah M.J.
      • Tangutur A.D.
      • Manyam R.R.
      Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy.
      ). 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.
      Figure thumbnail gr1
      Figure 1HDAC1/2 regulate epidermal homeostasis and promote progression of pre–basal cell carcinoma by inhibiting p53 and p16 in keratinocytes. The study by
      • Zhu X.
      • Leboeuf M.
      • Liu F.
      • Grachtchouk M.
      • Seykora J.T.
      • Morrisey E.E.
      • et al.
      HDAC1/2 control proliferation and survival in adult epidermis and pre–basal cell carcinoma through p16 and p53.
      highlights the role of HDAC1/2 in promoting epidermal proliferation and inhibiting senescence and apoptosis in the normal homeostatic epidermis and in pre–basal cell carcinoma via regulation of p53 and p16 activities.

      ORCIDs

      Vladimir A. Botchkarev: http://orcid.org/0000-0002-5212-5353

      Conflict of Interest

      The authors state no conflict of interest.

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      Linked Article

      • HDAC1/2 Control Proliferation and Survival in Adult Epidermis and Pre‒Basal Cell Carcinoma through p16 and p53
        Journal of Investigative DermatologyVol. 142Issue 1
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          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.
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