Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function
. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes ...KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)
. KAT6A has essential roles in normal haematopoietic stem cells
and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia
. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers
. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus
, a function that requires its KAT activity
. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days
. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.
Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that impede the growth and/or survival of tumor cells. Depending on the physiological context, HDACi can induce ...apoptosis via two well-defined apoptotic pathways; the intrinsic/mitochondrial pathway and the death receptor (DR)/extrinsic pathway. A number of groups have demonstrated that overexpression of prosurvival Bcl-2 family members significantly reduces HDACi-mediated tumor cell death and therapeutic efficacy in preclinical models. In many cases, HDACi activate the intrinsic pathway via upregulation of a number of proapoptotic BH3-only Bcl-2 family genes including Bim, Bid, and Bmf. Additionally, HDACi can engage the extrinsic pathway through upregulation of DR expression, reductions in c-FLIP, and upregulation of ligands such as TRAIL. Overall, it appears that activation of the intrinsic apoptotic pathway is the predominant mechanism of HDACi-induced tumor cell death; however, the DR pathway may also be engaged, either to amplify the apoptotic signal through the intrinsic pathway or to directly induce cell death.
Histone deacetylase inhibitors in cancer therapy Rasheed, Walid K; Johnstone, Ricky W; Prince, H Miles
Expert opinion on investigational drugs,
05/2007, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Histones are a family of nuclear proteins that interact with DNA, resulting in DNA being wrapped around a core of histone octamer within the nucleosome. Acetylation/deacetylation of histones is an ...important mechanism that regulates gene expression and chromatin remodeling. Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic drugs that regulate gene expression by enhancing the acetylation of histones, and thus inducing chromatin relaxation and altering gene expression. HDAC inhibitors have been shown in preclinical studies to have potent anticancer activities. A range of structurally diverse HDAC inhibitors have been purified as natural products or synthetically produced. Due to the promising preclinical activity of these agents, numerous clinical trials have been initiated. In this review, the results of published data of single agent and combination trials of these drugs are reviewed, with a focus on dosing, scheduling and toxicity. Although still early in drug development, there is a picture that is starting to develop as to the common toxicities and which tumors seem to be the most susceptible to this class of drugs.
Purpose: Histone deacetylase inhibitors can alter gene expression and mediate diverse antitumor activities. Herein, we report the
safety and activity of the histone deacetylase inhibitor panobinostat ...(LBH589) in cutaneous T-cell lymphoma (CTCL) and identify
genes commonly regulated by panobinostat.
Experimental Design: Panobinostat was administered orally to patients with CTCL on Monday, Wednesday, and Friday of each week on a 28-day cycle.
A dose of 30 mg was considered excessively toxic, and subsequent patients were treated at the expanded maximum tolerated dose
of 20 mg. Biopsies from six patients taken 0, 4, 8, and 24 h after administration were subjected to microarray gene expression
profiling and real-time quantitative PCR of selected genes.
Results: Patients attained a complete response ( n = 2), attained a partial response ( n = 4), achieved stable disease with ongoing improvement ( n = 1), and progressed on treatment ( n = 2). Microarray data showed distinct gene expression response profiles over time following panobinostat treatment, with
the majority of genes being repressed. Twenty-three genes were commonly regulated by panobinostat in all patients tested.
Conclusions: Panobinostat is well tolerated and induces clinical responses in CTCL patients. Microarray analyses of tumor samples indicate
that panobinostat induces rapid changes in gene expression, and surprisingly more genes are repressed than are activated.
A unique set of genes that can mediate biological responses such as apoptosis, immune regulation, and angiogenesis were commonly
regulated in response to panobinostat. These genes are potential molecular biomarkers for panobinostat activity and are strong
candidates for the future assessment of their functional role(s) in mediating the antitumor responses of panobinostat.
Summary
The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this ...clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents.
Histone deacetylase inhibitors (HDACis) are known to exert immunomodulatory effects. We have recently demonstrated that the therapeutic efficacy of HDACis against aggressive B-cell lymphoma and colon ...carcinoma relies on a functional immune system, in particular on the production of interferon γ (IFNγ). Our findings provide a rationale for the combination of HDACis with immunotherapeutic agents in the clinic.
Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) ...transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs.
•Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens.•CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.
Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These ...compounds can also mediate immune-modulatory effects that may contribute to their anticancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes. We therefore sought to clarify the role of the immune system in mediating the efficacy of HDACi in a physiologic setting, using preclinical, syngeneic murine models of hematologic malignancies and solid tumors. We showed an intact immune system was required for the robust anticancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, although HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor bearing, HDACi-treated wild-type (WT) mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-γ and tumor cell signaling through IFN-γR were particularly important for the anticancer effects of HDACi, and vorinostat and IFN-γ acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with α-galactosylceramide (α-GalCer), an IFN-γ-inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not natural killer cells or CD8(+) T cells, were implicated as effectors of the vorinostat antitumor immune response. Together, our data suggest HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic.
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