Dysregulation of the epigenome drives aberrant transcriptional programmes that promote cancer onset and progression. Although defective gene regulation often affects oncogenic and tumour-suppressor ...networks, tumour immunogenicity and immune cells involved in antitumour responses may also be affected by epigenomic alterations. This could have important implications for the development and application of both epigenetic therapies and cancer immunotherapies, and combinations thereof. Here, we review the role of key aberrant epigenetic processes - DNA methylation and post-translational modification of histones - in tumour immunogenicity, as well as the effects of epigenetic modulation on antitumour immune cell function. We emphasize opportunities for small-molecule inhibitors of epigenetic regulators to enhance antitumour immune responses, and discuss the challenges of exploiting the complex interplay between cancer epigenetics and cancer immunology to develop treatment regimens combining epigenetic therapies with immunotherapies.
Interferons (IFNs) were discovered as cytokines induced during and protecting from viral infection. They have been documented to play essential roles in numerous physiological processes beyond ...antiviral and antimicrobial defense, including immunomodulation, cell cycle regulation, cell survival, and cell differentiation. Recent data have also uncovered a potentially darker side to IFN, including roles in inflammatory diseases, such as autoimmunity and diabetes. IFN can have effects in the absence of acute infection, highlighting a physiologic role for constitutive IFN. Type I IFNs are constitutively produced at vanishingly low quantities and yet exert profound effects, mediated in part through modulation of signaling intermediates required for responses to diverse cytokines. We review evidence for a yin-yang of IFN function through its role in modulating crosstalk between multiple cytokines by both feedforward and feedback regulation of common signaling intermediates and postulate a homeostatic role for IFN through tonic signaling in the absence of acute infection.
Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in ...melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
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► Electrostatic attraction underlies innate dsDNA recognition by the HIN domains ► Both OB folds and the linker between them engage the dsDNA backbone ► An autoinhibited state of AIM2 is activated by DNA that liberates the PYD domain ► DNA serves as an oligomerization platform for the inflammasome assembly
Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered ...expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators--histone deacetylases (HDACs)--and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner ...proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.
Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that ...rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.
► Hematologic cancer cell survival is dependent on activated Pol I transcription ► CX-5461, a selective inhibitor of Pol I, treats hematologic cancers in mice ► CX-5461 selectively kills tumor cells by activating p53-dependent apoptosis ► CX-5461 shows potent antiproliferative capacity in human hematologic tumor cells
Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals ...that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In addition to well-characterized genetic abnormalities that lead to cancer onset and progression, it is now recognized that
alterations to the epigenome may also play a significant role in ...oncogenesis. As a result, epigenetic-modulating agents such
as histone deacetylase inhibitors (HDACi) have attracted enormous attention as anticancer drugs. In numerous in vitro and preclinical settings, these compounds have shown their vast potential as single agent anticancer therapies, but unfortunately
equivalent responses have not always been observed in patients. Given the pleiotropic effects HDACi have on malignant cells,
their true therapeutic potential most likely lies in combination with other anticancer drugs. In this review we will focus
on the anticancer effects of HDACi when combined with other cancer therapeutics with an emphasis on those combinations based
on a strong molecular rationale.
The opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) allow gene expression to be exquisitely regulated through chromatin remodelling. Aberrant transcription due ...to altered expression or mutation of genes that encode HATs, HDACs or their binding partners, is a key event in the onset and progression of cancer. HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of tumour cells. The remarkable tumour specificity of these compounds, and their potency in vitro and in vivo, underscore the potential of HDAC inhibitors as exciting new agents for the treatment of cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Posttranslational modifications to histones affect chromatin structure and function resulting in altered gene expression and
changes in cell behavior. Aberrant gene expression and altered epigenomic ...patterns are major features of cancer. Epigenetic
changes including histone acetylation, histone methylation, and DNA methylation are now thought to play important roles in
the onset and progression of cancer in numerous tumor types. Indeed dysregulated epigenetic modifications, especially in early
neoplastic development, may be just as significant as genetic mutations in driving cancer development and growth. The reversal
of aberrant epigenetic changes has therefore emerged as a potential strategy for the treatment of cancer. A number of compounds
targeting enzymes that regulate histone acetylation, histone methylation, and DNA methylation have been developed as epigenetic
therapies, with some demonstrating efficacy in hematological malignancies and solid tumors. This review highlights the roles
of epigenetic modifications to histones and DNA in tumorigenesis and emerging epigenetic therapies being developed for the
treatment of cancer. Mol Cancer Ther 2009;8(6):1409–20
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