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(searched for: doi:10.3816/clml.2011.n.036)
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Ryan A. Denu
Sirtuin Biology in Cancer and Metabolic Disease pp 233-258; doi:10.1016/b978-0-12-822467-0.00012-7

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Stephan J Matissek, , Mona Karbalivand, Mohamed Sayed, Brendan M Reilly, Shayna Mallat, Shimaa M Ghazal, Manit Munshi, Guang Yang, , et al.
Published: 1 January 2021
Epigenomics, Volume 13, pp 129-144; doi:10.2217/epi-2020-0189

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Xin Lu, Pengfei Yang, Xinrui Zhao, Mingzu Jiang, Sijun Hu, Yanan Ouyang, Li Zeng,
Published: 1 September 2019
Experimental Cell Research, Volume 382; doi:10.1016/j.yexcr.2019.06.028

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Xiaodan Sun, Shouhan Wang, Junda Gai, Jingqian Guan, Ji Li, Yizhuo Li, Jinming Zhao, , Lin Fu, Qingchang Li
Published: 13 August 2019
Frontiers in Oncology, Volume 9; doi:10.3389/fonc.2019.00754

Abstract:
Sirtuin 5 (SIRT5), a mitochondrial class III NAD-dependent deacetylase, plays controversial roles in tumorigenesis and chemoresistance. Accordingly, its role in ovarian cancer development and drug resistance is not fully understood. Here, we demonstrate that SIRT5 is increased in ovarian cancer tissues compared to its expression in normal tissues and this predicts a poor response to chemotherapy. SIRT5 levels were also found to be higher in cisplatin-resistant SKOV-3 and CAOV-3 ovarian cancer cells than in cisplatin-sensitive A2780 cells. Furthermore, this protein was revealed to facilitate ovarian cancer cell growth and cisplatin-resistance in vitro. Mechanistically, we show that SIRT5 contributes to cisplatin resistance in ovarian cancer by suppressing cisplatin-induced DNA damage in a reactive oxygen species (ROS)-dependent manner via regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.
Luis Filipe Costa-Machado,
Published: 25 July 2019
Cell Cycle, Volume 18, pp 2164-2196; doi:10.1080/15384101.2019.1634953

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, , , Miguel Inacio Da Silva Filho, Niels Weinhold, Markus M. Nöthen, Per Hoffman, Uta Bertsch, Stefanie Huhn, Gareth J. Morgan, et al.
Communications Biology, Volume 2, pp 1-10; doi:10.1038/s42003-019-0329-2

Abstract:
Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, TH17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response. Subhayan Chattopadhyay et al. conduct genome-wide interaction studies to identify genetic susceptibility to multiple myeloma. They find 16 unique interacting loci, which implicate immune response in multiple myeloma pathology.
Dustin Carroll, Daret K. St. Clair
Antioxidants & Redox Signaling, Volume 29, pp 1612-1632; doi:10.1089/ars.2017.7326

Abstract:
Significance: The long-term hematopoietic stem cell (LT-HSC) demonstrates characteristics of self-renewal and the ability to manage expansion of the hematopoietic compartment while maintaining the capacity for differentiation into hematopoietic stem/progenitor cell (HSPC) and terminal sub-populations. Deregulation of the HSPC redox environment results in loss of signaling that normally controls HSPC fate, leading to a loss of HSPC function and exhaustion. The characteristics of HSPC exhaustion via redox stress closely mirror phenotypic traits of hematopoietic malignancies and the leukemic stem cell (LSC). These facets elucidate the HSC/LSC redox environment as a druggable target and a growing area of cancer research. Recent Advances: While myelosuppression and exhaustion of the hematopoietic niche are detrimental side effects of classical chemotherapies, new agents that modify the HSPC/LSC redox environment have demonstrated the potential for protection of normal HSPC function while inducing cytotoxicity within malignant populations. Critical Issues: New therapies must preserve, or only slightly disturb normal HSPC redox balance and function, while simultaneously altering the malignant cellular redox state. The cascade nature of redox damage makes this a critical and delicate line for the development of a redox based therapeutic index. Future Directions: Recent evidence demonstrates the potential for redox based therapies to impact metabolic and epigenetic factors that could contribute to initial LSC transformation. This is balanced by the development of therapies that protect HSPC function. This pushes towards therapies that may alter the HSC/LSC redox state but lead to initiation cell fate signaling lost in malignant transformation while protecting normal HSPC function.
, David B. Lombard
Critical Reviews in Biochemistry and Molecular Biology, Volume 53, pp 311-334; doi:10.1080/10409238.2018.1458071

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Antioxidants & Redox Signaling, Volume 28, pp 677-690; doi:10.1089/ars.2017.7264

Abstract:
Significance: Developing evidence in the literature suggests that SIRT5 may be involved in metabolic reprogramming, an emerging hallmark of cancer by which neoplastic cells reconfigure their metabolism to support the anabolic demands of rapid cell division. Sirtuin 5 (SIRT5) is one of the seven members of the nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin family of lysine deacylases. It removes succinyl, malonyl, and glutaryl groups from protein targets within the mitochondrial matrix and other subcellular compartments. SIRT5’s substrates include a number of proteins integral to metabolism. Recent Advances: New work has begun to elucidate the roles of SIRT5 in glycolysis, TCA cycle, FAO, nitrogen metabolism, pentose phosphate pathway, antioxidant defense, and apoptosis. Critical Issues: Here, we summarize biological functions of SIRT5 reported in normal tissues and in cancer, and discuss potential mechanisms whereby SIRT5 may impact tumorigenesis, particularly focusing on its reported roles in metabolic reprogramming. Finally, we review current efforts to target SIRT5 pharmacologically. Future Directions: The biological significance of SIRT5 has been elucidated in the context of only an extremely small fraction of its targets and interactors. No doubt further studies in this area will provide a wealth of insights into functions of SIRT5 and its targets in normal and neoplastic cells.
, Gloria Figueroa, Tiyash Parira, Adriana Yndart, Karla Muñoz, , Thangavel Samikkannu, Madhavan P. Nair
Published: 1 June 2016
PLoS ONE, Volume 11; doi:10.1371/journal.pone.0156421

Abstract:
Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed. Additionally, MDDCs treated with alcohol were assessed using qRT-PCR, western blot, and fluorometric assay. The functional effects of alcohol-induce oxidative stress were measured in vitro using PCR array and in silico using gene expression network analysis. Our findings show, for the first time, that MDDCs from self-reported alcohol users have higher levels of class I HDACs compare to controls and alcohol treatment in vitro differentially modulates HDACs expression. Further, HDAC inhibitors (HDACi) blocked alcohol-induction of class I HDACs and modulated alcohol-induced oxidative stress related genes expressed by MDDCs. In silico analysis revealed new target genes and pathways on the mode of action of alcohol and HDACi. Findings elucidating the ability of alcohol to modulate class I HDACs may be useful for the treatment of alcohol-induced oxidative damage and may delineate new potential immune-modulatory mechanisms.
Jeffrey Lopez, Eric D. Sullivan,
ACS Chemical Biology, Volume 11, pp 706-716; doi:10.1021/acschembio.5b01067

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Veronica S. Gil, , Louise Howell, Jiyuan Zhang, Chae H. Kim, Sven Stengel, , Arthur Zelent,
Disease Models & Mechanisms, Volume 9, pp 1483-1495; doi:10.1242/dmm.023366

Abstract:
Histone Deacetylase 9 (HDAC9) is expressed in B-cells and its overexpression has been observed in B-lymphoproliferative disorders and B-cell non-Hodgkin lymphomas (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here we report that the Eμ-HDAC9 GEM model developed splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal centre cell origin in common with human tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 may contribute to lymphomagenesis by altering pathways involved in growth and survival as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B- cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, pre-clinical testing of therapeutic approaches based on histone deacetylase inhibitors.
Published: 6 February 2013
Leukemia, Volume 27, pp 762-772; doi:10.1038/leu.2013.36

Abstract:
Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Bruna Barneda-Zahonero,
Published: 27 August 2012
Molecular Oncology, Volume 6, pp 579-589; doi:10.1016/j.molonc.2012.07.003

Abstract:
Reversible acetylation of histone and non-histone proteins is one of the most abundant post-translational modifications in eukaryotic cells. Protein acetylation and deacetylation are achieved by the antagonistic actions of two families of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). Aberrant protein acetylation, particularly on histones, has been related to cancer while abnormal expression of HDACs has been found in a broad range of cancer types. Therefore, HDACs have emerged as promising targets in cancer therapeutics, and the development of HDAC inhibitors (HDIs), a rapidly evolving area of clinical research. However, the contributions of specific HDACs to a given cancer type remain incompletely understood. The aim of this review is to summarize the current knowledge concerning the role of HDACs in cancer with special emphasis on what we have learned from the analysis of patient samples.
Jenny Y. Sun, Hsiuyi Tseng, Lian Xu, , Bryan Ciccarelli, Mariateresa Fulciniti, Bangmin Zhu, Kaveh Maghsoudi, Guang Yang, Ping Gong, et al.
Published: 10 June 2011
Leukemia & Lymphoma, Volume 52, pp 1777-1786; doi:10.3109/10428194.2011.577850

The publisher has not yet granted permission to display this abstract.
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