Sirtuins (SIRTs), class III histone deacetylases, are differentially expressed in several human cancers, where they display both oncogenic and tumor-suppressive properties depending on cellular ...context and experimental conditions. SIRTs are involved in many important biological processes and play a critical role in cancer initiation, promotion, and progression. A growing body of evidence indicates the involvement of SIRTs in regulating three important tumor processes: epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. Many SIRTs are responsible for cellular metabolic reprogramming and drug resistance by inactivating cell death pathways and promoting uncontrolled proliferation. In this review, we summarize current knowledge on the role of SIRTs in cancer and discuss their puzzling dual function as tumor suppressors and tumor promoters, important for the future development of novel tailored SIRT-based cancer therapies.
Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood.
Using ...gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines.
, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to
activation and apoptosis. c-Myc binds to the
promoter on the proximal GC box through SP1 or MIZ1, impairing
activation. HDACi exposure triggers
expression, altering c-Myc-
binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment
of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed
in AML patients undergoing HDACi-based clinical trials.
Collectively, our findings identify a key role for c-Myc in
deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies.
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is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of
gene expression and/or an increase in MYC protein ...stability.
overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.
The aim of this Special Issue on the deregulation of cell death in cancer is to bring together recent perspectives on the relationship between tumorigenesis and programmed cell death (PCD) ....
Sirtuins are NAD(+)-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, ...senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.
The Two-Faced Role of SIRT6 in Cancer Fiorentino, Francesco; Carafa, Vincenzo; Favale, Gregorio ...
Cancers,
03/2021, Letnik:
13, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Sirtuin 6 (SIRT6) is a NAD
-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly ...key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic homeostasis, and apoptosis. SIRT6 regulates the expression and activity of both pro-apoptotic (e.g., Bax) and anti-apoptotic factors (e.g., Bcl-2, survivin) in a context-depending manner. Mounting evidence points towards a double-faced involvement of SIRT6 in tumor onset and progression since the block or induction of apoptosis lead to opposite outcomes in cancer. Here, we discuss the features and roles of SIRT6 in the regulation of cell death and cancer, also focusing on recently discovered small molecule modulators that can be used as chemical probes to shed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics.
Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.
We have investigated the role of RIP1 and ...the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and
studies with different mice models.
Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential
, in leukemic blasts
and
in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation
These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention.
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Plants produce a vast array of biomolecules with beneficial effects for human health. In this study, polyphenol and anthocyanin-rich extracts (PAE) from pigmented tubers of
L. varieties "Blue Star", ..."Magenta Love", and "Double Fun" in comparison with the more extensively studied "Vitelotte" were evaluated and compared for antiproliferative effects in human leukemia cells, and their phytochemical and genetic profiles were determined. In U937 cells, upon treatment with PAE, it was possible to reveal the expression of specific apoptotic players, such as caspase 8, 9, 3, and poly (ADP-ribose) polymerase (PARP), as well as the induction of monocyte and granulocyte differentiation. A liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) investigation revealed the presence of polyphenolic compounds in all the varieties of potatoes analyzed, among which caffeoyl and feruloyl quinic acid derivatives were the most abundant, as well as several acylated anthocyanins. Each pigmented variety was genotyped by DNA-based molecular markers, and flavonoid-related transcription factors were profiled in tubers in order to better characterize these outstanding resources and contribute to their exploitation in breeding. Interesting biological activities were observed for "Blue Star" and "Vitelotte" varieties with respect to the minor or no effect of the "Double Fun" variety.
Sirt2 is a target for the treatment of neurological, metabolic, and age-related diseases including cancer. Here we report a series of Sirt2 inhibitors based on the 1,2,4-oxadiazole scaffold. These ...compounds are potent Sirt2 inhibitors active at single-digit μM level by using the Sirt2 substrate α-tubulin-acetylLys40 peptide and inactive up to 100 μM against Sirt1, -3, and -5 (deacetylase and desuccinylase activities). Their mechanism of inhibition is uncompetitive toward both the peptide substrate and NAD+, and the crystal structure of a 1,2,4-oxadiazole analog in complex with Sirt2 and ADP-ribose reveals its orientation in a still unexplored subcavity useful for further inhibitor development. Tested in leukemia cell lines, 35 and 39 induced apoptosis and/or showed antiproliferative effects at 10 or 25 μM after 48 h. Western blot analyses confirmed the involvement of Sirt2 inhibition for their effects in NB4 and in U937 cells. Our results provide novel Sirt2 inhibitors with a compact scaffold and structural insights for further inhibitor improvement.
Acetylation of histone and non-histone proteins is a post-translational modification mostly associated with activation of gene transcription. The first histone acetyltransferase (HAT) identified as ...modifying newly synthesized histone H4 in yeast was a type B HAT named HAT1. Although it was the first HAT to be discovered, HAT1 remains one of the most poorly studied enzymes in its class. In addition to its well-established role in the cytoplasm, recent findings have revealed new and intriguing aspects of the function of HAT1 in the nucleus. Several studies have described its involvement in regulating different pathways associated with a wide range of diseases, including cancer. This review focuses on our current understanding of HAT1, highlighting its importance in regulating chromatin replication and gene expression. This previously unknown role for HAT1 opens up novel scenarios in which further studies will be required to better understand its function.
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