Aop: 212

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Histone deacetylase inhibition leading to testicular atrophy

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Histone deacetylase inhibition leading to testicular atrophy

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Shihori Tanabe, Akihiko Hirose, Takashi Yamada

Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Japan

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Shihori Tanabe   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Shihori Tanabe

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for citation & comment WPHA/WNT Endorsed 1.52 Included in OECD Work Plan
This AOP was last modified on November 02, 2021 14:58

Revision dates for related pages

Page Revision Date/Time
Histone deacetylase inhibition July 14, 2022 16:18
Histone acetylation, increase July 28, 2021 00:10
Cell cycle, disrupted June 30, 2021 02:56
Apoptosis August 05, 2021 19:35
Testicular atrophy July 01, 2021 01:55
Spermatocyte depletion July 28, 2021 02:14
Histone deacetylase inhibition leads to Histone acetylation, increase August 05, 2021 19:32
Histone acetylation, increase leads to Cell cycle, disrupted July 01, 2021 03:28
Cell cycle, disrupted leads to Apoptosis July 28, 2021 01:28
Histone deacetylase inhibition leads to Cell cycle, disrupted July 28, 2021 01:32
Apoptosis leads to Spermatocyte depletion July 28, 2021 01:31
Histone deacetylase inhibition leads to Apoptosis July 01, 2021 21:38
Spermatocyte depletion leads to Testicular atrophy July 28, 2021 00:45
Histone deacetylase inhibition leads to Spermatocyte depletion July 01, 2021 21:43
Histone deacetylase inhibition leads to Testicular atrophy July 28, 2021 01:33
Methoxyacetic acid January 21, 2018 20:38
Butyrate January 21, 2018 20:39
Trichostatin A January 21, 2018 20:39
Valproate November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Testicular toxicity is of interest for human health risk assessment especially in terms of reproductive and developmental toxicity, however, the testicular toxicity has not been fully elucidated. Histone deacetylase inhibitors (HDIs) are approved as anti-cancer drugs since HDIs have apoptotic effects in cancer cells. HDIs include short-chain fatty acids, hydroxamic acids, benzamides, and epoxides. The intracellular mechanisms of induction of the spermatocyte apoptosis by HDIs are suggested as histone deacetylase (HDAC) inhibition as MIE, histone acetylation increase, disrupted cell cycle, apoptosis, and spermatocyte depletion as KEs. The adverse outcome has been defined as testicular atrophy. The HDIs inhibit deacetylation of the histone, leading to an increase in histone acetylation. The apoptosis induced by the disrupted cell cycle leads to spermatocyte depletion and testis atrophy. This AOP may be one of the pathways induced by HDIs, which suggests the pathway networks of protein hyperacetylations.

[Abbreviation] AOP: adverse outcome pathway, HDAC: histone deacetylase, HDI: HDAC inhibitor, KE: key event, MIE: molecular initiating event, MAA: 2-Methoxyacetic acid, or Methoxyacetic acid

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1502 Histone deacetylase inhibition Histone deacetylase inhibition
KE 1503 Histone acetylation, increase Histone acetylation, increase
KE 1505 Cell cycle, disrupted Cell cycle, disrupted
KE 1262 Apoptosis Apoptosis
KE 1515 Spermatocyte depletion Spermatocyte depletion
AO 1506 Testicular atrophy Testicular atrophy

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adult, reproductively mature High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Male High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help
Attached file: Overallassessmentaop212rev 2 10 20

1. Support for Biological Plausibility of KERs

MIE => KE1: Histone deacetylase inhibition leads to histone acetylation increase

Biological Plausibility of the MIE => KE1 is high. Rationale: Upon the inhibition of HDAC by HDIs, the acetylation of lysine in histone remains and it leads to transcriptional activation or repression, changes in DNA replication, and DNA damage repair. The activity of histone acetyltransferase (HAT) in testis nuclear protein was increased with MAA addition [Wade et al., 2008].

KE1 => KE2: Histone acetylation, increase leads to cell cycle, disrupted

Biological Plausibility of the KE1 => KE2 is moderate. Rationale: Gene transcription is regulated by histone acetylation [Struhl, 1998]. Acetylation of histones neutralizes the positive charge of the histones. Thus, less compacted DNA can be bound more easily by transcription factors and transcribed. In the models proposed for the relationship between histone acetylation and transcription, histone acetylation can be untargeted and occur at both promoter and non-promoter regions, targeted generally to promoter regions, or targeted to specific promoters by gene-specific activator proteins [Richon et al., 2000; Struhl, 1998].

KE2 => KE3: Cell cycle, disrupted leads to apoptosis

Biological Plausibility of the KE2 => KE3 is moderate. Rationale: Prolonged cell cycle arrest will lead to either senescence or apoptosis. Especially for fast-dividing and still differentiating cells, such an arrest will most certainly induce apoptosis as the normal cellular program cannot be followed.

KE3 => KE4: Apoptosis leads to spermatocyte depletion

Biological Plausibility of the KE3 => KE4 is moderate. Rationale: During development and in tissue homeostasis, apoptosis is needed to control organ size. If apoptosis is induced at a higher rate, one can assume it leading to atrophy of the target organ. Especially when target organ/target cells are fast replicating, abnormal levels of apoptosis will lead to depletion.

KE4 => AO: Spermatocyte depletion leads to testicular atrophy

Biological Plausibility of the KE4 => AO is moderate. Rationale: Spermatocyte depletion is one of the main characteristics of testicular atrophy.

2. Support for Essentiality of KEs

KE2: Cell cycle, disrupted

The essentiality of the KE2 is moderate. The rationale for the Essentiality of KEs in the AOP: HDAC1-deficient embryonic stem cells showed reduced proliferation rates, which correlates with decreased cyclin-associated kinase activities and elevated levels of the cyclin-dependent kinase inhibitor 1A, a cell cycle regulator p21 [Lagger et al., 2002]. Loss of HDAC1 leads to significantly reduced overall deacetylase activity, hyperacetylation of a subset of histones H3 and H4 [Lagger et al., 2002].

3. Empirical Support for KERs

MIE => KE1: Histone deacetylase inhibition leads to histone acetylation, increase

Empirical Support of the MIE => KE1 is high. Rationale: HDAC inhibitors increase histone acetylation in the brain [Schroeder et al., 2013]. The major empirical evidence came from the incubation of cell culture cells with small molecule compounds that inhibit HDAC enzymes followed by western blots or acid urea gel analysis. The first evidence was shown by Riggs et al. who showed that incubation of HeLa cells with n-butyrate leads to an accumulation of acetylated histone proteins [Riggs et al., 1977]. Later, it was shown that n-butyrate specifically increases the acetylation of histone by the incorporation of radioactive [3H]acetate and analysis of the histones on acid urea gels that allow the detection of acetylated histones [Cousens et al., 1979]. TSA was shown to be an HDAC inhibitor by acid urea gel analysis in 1990 [Yoshida et al., 1990] and good evidence for VPA as an HDAC inhibitor in vitro and in vivo was shown using acetyl-specific antibodies and western blot [Gottlicher et al., 2001].

KE1 => KE2: Histone acetylation, increase leads to cell cycle, disrupted

Empirical Support of the KE1 => KE2 is moderate. Rationale: Increase in histone acetylation by HDAC inhibition induces the cell cycle regulator expression and inhibits progression through the cell cycle. Histone acetylation regulates the gene transcriptional mechanism [Struhl, 1998]. Acetylation of histones promotes the RNA polymerase reaction [Allfrey et al., 1964; Pogo et al., 1966]. Since several results supported a model in which increased histone acetylation is targeted to a specific gene and occurs throughout the entire genome, not just the promoter regions, histone acetylation may lead to gene transcription of the cell cycle regulator [Richon et al., 2000].

KE2 => KE3: Cell cycle, disrupted leads to apoptosis

Empirical Support of the KE2 => KE3 is moderate. Rationale: Cell cycle arrests such as G1 arrest and G1/S arrest are observed in apoptosis [Li et al., 2012; Dong et al., 2010]. microRNA-1 and microRNA-206 repress CCND2, while microRNA-29 represses CCND2 and induces G1 arrest and apoptosis in rhabdomyosarcoma [Li et al., 2012].

KE3 => KE4: Apoptosis leads to spermatocyte depletion

Empirical Support of the KE3 => KE4 is high. Rationale: microRNA-21 regulates the spermatogonial stem cell homeostasis, in which suppression of microRNA-21 with anti-miR-21 oligonucleotides led to apoptosis of spermatogonial stem cell-enriched germ cell cultures and the decrease in the number of spermatogonial stem cells [Niu et al., 2011].

KE4 => AO: Spermatocyte depletion leads to testicular atrophy

Empirical Support of the KE4 => AO is high. Rationale: The testicular atrophy seen in 2-methoxyethanol (2-ME), or its major metabolite MAA, treated rats in vivo and in human, and rat in vitro culture was associated with spermatocyte depletion [Beattie et al., 1984].

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

The AOP is applicable to the reproductively mature males in rats, mice and humans. The administration route or doses of HDAC inhibitors may affect the intensity of the toxicity.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help
Key Event Direct/Indirect Evidence
MIE: Histone deacetylase inhibition HDAC inhibition induced testicular toxicity including testis atrophy [Miller et al., 1982]. HDAC inhibition in cell culture resulted in testicular toxicity including germ cell apoptosis and cell morphology change [Li et al., 1996].
KE1: Histone acetylation, increase The HDAC inhibition induced cell death in spermatocytes in both rat and human seminiferous tubules [Li et al., 1996].
KE2: Cell cycle, disrupted In HDAC1-/- fibroblast lines, an increase in the number of cells in the G1 phase and a decrease in the number of cells in the S phase were observed, which indicates the importance of HDAC inhibition in cell cycle regulation [Zupkovitz et al., 2010].
KE3: Apoptosis HDAC inhibition leads to cell death through the apoptotic pathways [Falkenberg et al., 2014].
KE4: Spermatocyte depletion The HDAC inhibition induced cell death in spermatocytes in both rat and human seminiferous tubules [Li et al., 1996]. The HDAC inhibitor treatment resulted in degeneration in spermatocytes in rat seminiferous tubules [Li et al., 1996]. The HDAC inhibition induced germ cell apoptosis in human testicular tissues [Li et al., 1996].

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Biological plausibility, coherence, and consistency of the experimental evidence

The available data supporting the AOP are logical, coherent, and consistent with established biological knowledge, whereas there are possibilities for alternative pathways.

 

Alternative mechanism(s) that logically present themselves and the extent to which they may distract from the postulated AOP

There are some other important apoptotic pathways that are involved in cell death, as well as other important spermatocyte signaling or mechanism influences testicular toxicity.

 

  • p53 pathway

The study in which in vivo administration of trichostatin A (TSA), an HDI, in mice resulted in male meiosis impairment showed the involvement of p53-noxa-caspase-3 apoptotic pathway in TSA-induced spermatocyte apoptosis [Fenic et al., 2008]. Another study showed that MAA-induced up-regulation of p21 expression is mediated through histone hyperacetylation and independent of p53/p63/p73 [Parajuli et al., 2014].

 

  • NF-kappaB pathway

The present AOP focuses on the p21 pathway leading to apoptosis, however, alternative pathways such as NF-kappaB signaling pathways may be involved in the apoptosis of spermatocytes [Wang et al., 2017].

 

  • Communication with Sertoli cells

The present AOP focuses on testicular atrophy by HDAC inhibition-induced apoptosis in spermatocytes, however, the signaling in Sertoli cells may be involved in testicular atrophy. Sertoli cell secretes GDNF, FGF2, CXCL12, or Ccl9 molecules, which results in the activation of RET, FGFR, CXCR4, or CCR1 signaling in spermatogonial stem cells, respectively [Chen and Liu, 2015].

 

  • Decrease in deoxynucleotide pool by MAA

MAA induces a decrease in the deoxynucleotide pool, resulting in apoptosis, which may be an alternative pathway other than the p21-mediated pathway [Yamazoe et al., 2015]. Inhibition of 5,10-CH2-THF production by MAA may decrease deoxynucleotide pool in spermatocytes [Yamazoe et al., 2015].

 

  • Spermatocyte depletion by necrosis

Spermatocyte may be decreased by necrosis. Cell death mechanisms other than apoptosis, such as necrosis, may be considered for spermatocyte depletion.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Concordance of dose-response relationships

This is a quantitative description of dose-response relationships from MIE to AOP. But some KE relationships individually are not fully supported with dose-response relationships, while there is empirical evidence to support that a change in KEup leads to an appropriate change in the respective KEdown.

 

Temporal concordance among the key events and adverse outcome

Temporal concordance between MIE and AOP has been described with in vivo experimental data. Empirical evidence shows temporal concordance between MIE and the individual KEs, however, the temporal concordance among the individual KEs and AO is not fully elucidated.

Strength, consistency, and specificity of association of adverse outcome and initiating event

The scientific evidence on the linkage between MIE and AO has been described.

The quantitative understanding of the AOP in terms of indirect relations between HDAC inhibition and testicular atrophy was examined in in vivo experiments [Foster et al., 1983; Miller et al., 1982].

 

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

The AOP may be useful in the risk assessment on several types of HDI molecules including anti-cancer drugs, as well as other types of chemicals, biocides, or pesticides. HDAC inhibitors nowadays have been utilized as therapeutics for cancer or neurology disease, and the adverse effects of HDAC inhibitors should be evaluated. This AOP elucidating the pathway from HDAC inhibition to testicular atrophy may provide important insights into the potential toxicity of HDAC inhibitors. It also provides a basis for the HDAC inhibition-induced epigenetic alteration and cell death. HDAC inhibitors such as rocilinostat/ricolinostat are clinically evaluated as anti-cancer drugs in clinical trials [Yee et al., 2016]. The AOP may be useful for the risk assessment of chemicals, since possible applications of HDAC inhibitors include the enhancement of salinity tolerance to increase agricultural sustainability. Other potential applications of the AOP include the risk assessment of biocides or pesticides, considering that HDAC inhibitors are being investigated as insecticides or amoebicides [Bagnall et al., 2017; Lee et al., 2020]. 

References

List of the literature that was cited for this AOP. More help

Allfrey, V. et al. (1964), "Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis", Proc Natl Acad Sci 51:786-794

Bagnall, N.H. et al. (2017), "Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina", Int J Parasitology: Drugs Drug Resistance 7(1):51–60 https://doi.org/10.1016/j.ijpddr.2017.01.001

Beattie, P.J. et al. (1984), "The effect of 2-methoxyethanol and methoxyacetic acid on Sertoli cell lactate production and protein synthesis in vitro", Toxicol Appl Pharmacol 76:56-61

Chen, S. and Liu, Y. (2015), "Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling", Reproduction 149:R159-R167

Cousens, L.S., et al. (1979), "Different accessibilities in chromatin to histone acetylase", J Biol Chem 254:1716-1723

Dong, Q. et al. (2010), "microRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2", PLoS One 5:e10147

Fenic, I. et al. (2008), "In vivo application of histone deacetylase inhibitor trichostatin-A impairs murine male meiosis", J Andro 29:172-185

Foster, P.M. et al. (1983), "Testicular toxicity of ethylene glycol monomethyl and monoethyl ethers in the rat", Toxicol Appl Pharmacol 69:385-39

Gottlicher, M. et al. (2001), "Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells", EMBO J 20:6969-6978

Lagger, G. et al. (2002), "Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression", EMBO J 21:2672-2681 

Lee, H-A. et al. (2020), "Application of histone deacetylase inhibitors MPK472 and KSK64 as a potential treatment option for Acanthamoeba keratitis" Antimicrob Agents Chemother 64:e01506-20 https://doi.org/10.1128/AAC.01506-20                                     

Li, L. et al. (2012), "Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma", Lab Invest 92:571-583  

Li, L.H. et al. (1996), "2-Methoxyacetic acid (MAA)-induced spermatocyte apoptosis in human and rat testes: an in vitro comparison", J Androl 17:538-549

Miller, R.R. et al. (1982), "Toxicity of methoxyacetic acid in rats", Fundam Appl Toxicol 2:158-160

Niu, Z. et al. (2011), "microRNA-21 regulates the self-renewal of mouse spermatogonial stem cells", Proc Natl Acad Sci 108:12740-12745

Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-312

Pogo, B. et al. (1966), "RNA synthesis and histone acetylation during the course of gene activation in lymphocytes", Proc Natl Acad Sci 55:805-812

Richon, V.M. et al. (2000), "Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation", Proc Natl Acad Sci 97:10014-10019        

Riggs, M.G. et al. (1977), "N-butyrate causes histone modification in HeLa and friend erythroleukaemia cells", Nature 268:462-464

Schroeder, F.A. et al. (2013), "A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests", PLoS One 8:e71323

Struhl, K. (1998), "Histone acetylation and transcriptional regulatory mechanisms", Gene Dev 12:599-606      

Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831

Wang, C. et al. (2017), "CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways", Oncotarget 8:3132-3143

Yamazoe, Y. et al. (2015), "Embryo- and testicular-toxicities of methoxyacetate and the related: a review on possible roles of one-carbon transfer and histone modification", Food Safety 3:92-107

Yee, A.J. et al. (2016), "Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial", Lancet Oncol 17(11):1569-1578 https://doi.org/10.1016/s1470-2045(16)30375-8

Yoshida, M. et al. (1990), "Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro trichostatin A", J Biol Chem 265:17174-17179

Zupkovitz, G. et al. (2010), "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation", Mol Cell Biol 30:1171-1181