bims-drucaf 2020-08-02 papers

bims-drucaf

Biomed News

on Drugs targeting chromatin associated factor in cancer therapy

Issue of 2020–08–02
ten papers selected by
Tian V. Tian, Vall d’Hebron Institute of Oncology

HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML.
The ups and downs of Poly(ADP-ribose) Polymerase-1 inhibitors in cancer therapy-Current progress and future direction.
A distal regulatory region of a class I human histone deacetylase.
Bromodomain Inhibitors as Therapeutics for Herpesvirus-Related Disease: All BETs Are Off?
Altered expression of epigenetic modifiers EZH2, H3K27me3, and DNA methyltransferases in meningiomas - prognostic biomarkers for routine practice.
Epigenetic regulation of cancer stem cell and tumorigenesis.
EZH2: a novel target for cancer treatment.
FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination.
Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer.
BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression.

Aging (Albany NY). 2020 Jul 29. 12

HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML.

Feiteng Huang, Jie Sun, Wei Chen, Xin He, Yinghui Zhu, Haojie Dong, Hanying Wang, Zheng Li, Lei Zhang, Samer Khaled, Guido Marcucci, Jinwen Huang, Ling Li.

  Aberrant DNA methylation often silences transcription of tumor-suppressor genes and is considered a hallmark of myeloid neoplasms. Similarly, histone deacetylation represses transcription of genes responsible for cell differentiation/death. A previous clinical study suggested potential pharmacodynamic antagonism between histone deacetylase inhibitors (HDACi) and DNA hypomethylating agents (HMA). Herein, to determine such antagonism, we used MDS/AML lines and NHD13 transgenic mice, and demonstrated that treatment with the pan-HDACi suberoylanilide hydroxamic acid (SAHA) significantly decreased TET2 expression and global 5-hydroxymethylcytosine (5hmC) levels. Mechanistically, our RNAi screen revealed that HDAC4 was responsible for maintaining TET2 levels. Accordingly, HDAC4 knockout reduced expression levels of MTSS1, a known TET2 target, an event associated with decreased 5hmC enrichment on the MTSS1 enhancer. Retrospective analysis of GEO datasets demonstrated that lower HDAC4 levels predict worse prognosis for AML patients. In an MDS-L xenografted immunodeficient mouse model, vitamin C co-treatment prevented TET2 loss of activity seen following SAHA treatment. Accordingly, vitamin C co-treatment further reduced MDS-L cell engraftment relative to SAHA alone. In summary, our findings suggest that co-administration of a TET2 agonist with pan-HDACi treatment could effectively counter potential diminution in TET2 activity resulting from pan-HDACi treatment alone, providing a rationale for evaluating such combinations against high-risk MDS/AML.

Keywords:  TET2; acute myeloid leukemia; histone deacetylase; myelodysplastic syndromes

DOI:  https://doi.org/10.18632/aging.103605
Eur J Med Chem. 2020 Jul 15. pii: S0223-5234(20)30542-0. [Epub ahead of print]203 112570

The ups and downs of Poly(ADP-ribose) Polymerase-1 inhibitors in cancer therapy-Current progress and future direction.

Yue Zhao, Liu-Xia Zhang, Ting Jiang, Jing Long, Zhong-Ye Ma, Ai-Ping Lu, Yan Cheng, Dong-Sheng Cao.

  Poly(ADP-ribose) Polymerase 1 (PARP1), one of the most investigated 18 membered PARP family enzymes, is involved in a variety of cellular functions including DNA damage repair, gene transcription and cell apoptosis. PARP1 can form a PARP1(ADP-ribose) polymers, then bind to the DNA damage gap to recruit DNA repair proteins, and repair the break to maintain genomic stability. PARP1 is highly expressed in tumor cells, so the inhibition of PARP1 can block DNA repair, promote tumor cell apoptosis, and exert antitumor activity. To date, four PARP1 inhibitors namely olaparib, rucaparib, niraparib and talazoparib, have been approved by Food and Drug Administration (FDA) for treating ovarian cancer and breast cancer with BRCA1/2 mutation. These drugs have showed super advantages over conventional chemotherapeutic drugs with low hematological toxicity and slowly developed drug resistance. In this article, we summarize and analyze the structure features of PARP1, the biological functions and antitumor mechanisms of PARP1 inhibitors. Importantly, we suggest that establishing a new structure-activity relationship of developed PARP1 inhibitors via substructural searching and the matched molecular pair analysis would accelerate the process in finding more potent and safer PARP1 inhibitors.

Keywords:  Cancer; DNA damage repair; Matched molecular pair; PARP1; PARP1 inhibitors; Structure-activity relationship

DOI:  https://doi.org/10.1016/j.ejmech.2020.112570
Nat Commun. 2020 Jul 31. 11(1): 3841

A distal regulatory region of a class I human histone deacetylase.

Nicolas D Werbeck, Vaibhav Kumar Shukla, Micha B A Kunze, Havva Yalinca, Ruth B Pritchard, Lucas Siemons, Somnath Mondal, Simon O R Greenwood, John Kirkpatrick, Charles M Marson, D Flemming Hansen.

Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.

DOI: https://doi.org/10.1038/s41467-020-17610-w
Front Cell Infect Microbiol. 2020 ;10 329

Bromodomain Inhibitors as Therapeutics for Herpesvirus-Related Disease: All BETs Are Off?

Ian J Groves, John H Sinclair, Mark R Wills.

  Although the ubiquitous human herpesviruses (HHVs) are rarely associated with serious disease of the healthy host, primary infection and reactivation in immunocompromised individuals can lead to significant morbidity and, in some cases, mortality. Effective drugs are available for clinical treatment, however resistance is on the rise such that new anti-viral targets, as well as novel clinical treatment strategies, are required. A promising area of development and pre-clinical research is that of inhibitors of epigenetic modifying proteins that control both cellular functions and the viral life cycle. Here, we briefly outline the interaction of the host bromo- and extra-terminal domain (BET) proteins during different stages of the HHVs' life cycles while giving a full overview of the published work using BET bromodomain inhibitors (BRDis) during HHV infections. Furthermore, we provide evidence that small molecule inhibitors targeting the host BET proteins, and BRD4 in particular, have the potential for therapeutic intervention of HHV-associated disease.

Keywords:  BET bromodomain inhibitor; epigenetics; herpesvirus; latency; reactivation; therapy

DOI:  https://doi.org/10.3389/fcimb.2020.00329
Folia Neuropathol. 2020 ;pii: 41184. [Epub ahead of print]58(2): 133-142

Altered expression of epigenetic modifiers EZH2, H3K27me3, and DNA methyltransferases in meningiomas - prognostic biomarkers for routine practice.

Swagatika Samal, Ashis Patnaik, Fakir Sahu, Suvendu Purkait.

   INTRODUCTION: Meningiomas comprises of a wide variety of histological entities with heterogeneous biological behaviour and prognosis. The plethora of genetic data are yet to produce relevant biomarkers for routine use. In contrast, epigenetic alterations are less elucidated.
MATERIAL AND METHODS: The expression of the key molecules involved in the two principal epigenetic systems, i.e. DNA methylation (DNA methyltransferases [DNMT-1, -3A and -3B]) and histone modification (Enhancer of Zeste homolog-2 [EZH2] and trimethyl histone-3 [H3K27me3]) were assessed in 149 cases of meningiomas (grade I - 102, grade II - 47) by immunohistochemistry.
RESULTS: Immunopositivity for EZH2 (38.3% vs. 6.0%) and negativity for H3K27me3 (10.6% vs. 1.0%) were significantly more common in grade II tumours. Both were associated with significantly higher proliferative activity. The majority of the cases of both grades showed expression of all three DNMTs. However, high expression of DNMT-1 was significantly more common in grade II tumours (87.8% vs. 66.2%). Expression of EZH2 and loss of H3K27me3 were associated with significantly shorter progression-free survival (hazard ratio [HR] = 4.07 and 0.24, respectively).
CONCLUSIONS: The key epigenetic regulators play important roles in the pathobiology of meningiomas. EZH2 positivity and H3K27me3 negativity are associated with aggressive tumour-biology and poor prognosis. Both these markers can easily be assessed by immunohistochemistry and can be incorporated in routine practice.

Keywords:   DNMT. Introduction; EZH2; H3K27me3; epigenetic; meningioma

DOI:  https://doi.org/10.5114/fn.2020.96970
Adv Cancer Res. 2020 ;pii: S0065-230X(20)30043-9. [Epub ahead of print]148 1-26

Epigenetic regulation of cancer stem cell and tumorigenesis.

Kezhou Zhu, Victoria Xie, Suyun Huang.

  As a unique subpopulation of cancer cells, cancer stem cells (CSCs) acquire the resistance to conventional therapies and appear to be the prime cause of cancer recurrence. Like their normal counterparts, CSCs can renew themselves and generate differentiated progenies. Cancer stem cells are distinguished among heterogenous cancer cells by molecular markers and their capacity of efficiently forming new tumors composed of diverse and heterogenous cancer cells. Tumor heterogeneity can be inter- or intra-tumor, molecularly resulting from the accumulation of genetic and non-genetic alterations. Non-genetic alterations are mainly changes on epigenetic modifications of DNA and histone, and chromatin remodeling. As tumor-initiating cells and contributing to the tumor heterogeneity in the brain, glioblastoma stem cells (GSCs) attract extensive research interests. Epigenetic modifications confer on tumor cells including CSCs reversible and inheritable genomic changes and affect gene expression without alteration in DNA sequence. Here, we will review recent advances in histone demethylation, DNA methylation, RNA methylation and ubiquitination in glioblastomas and their impacts on tumorigenesis with a focus on CSCs.

Keywords:  Epigenetic regulation; Gene expression; Glioblastoma stem cell; Tumorigenesis

DOI:  https://doi.org/10.1016/bs.acr.2020.05.001
J Hematol Oncol. 2020 Jul 28. 13(1): 104

EZH2: a novel target for cancer treatment.

Ran Duan, Wenfang Du, Weijian Guo.

  Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

Keywords:  Cancer; EZH2; EZH2 inhibitor; H3K27me3

DOI:  https://doi.org/10.1186/s13045-020-00937-8
Proc Natl Acad Sci U S A. 2020 Jul 27. pii: 202009237. [Epub ahead of print]

FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination.

Elaine Guo, Yuki Ishii, James Mueller, Anjana Srivatsan, Timothy Gahman, Christopher D Putnam, Jean Y J Wang, Richard D Kolodner.

  Synthetic lethality strategies for cancer therapy exploit cancer-specific genetic defects to identify targets that are uniquely essential to the survival of tumor cells. Here we show RAD27/FEN1, which encodes flap endonuclease 1 (FEN1), a structure-specific nuclease with roles in DNA replication and repair, and has the greatest number of synthetic lethal interactions with Saccharomyces cerevisiae genome instability genes, is a druggable target for an inhibitor-based approach to kill cancers with defects in homologous recombination (HR). The vulnerability of cancers with HR defects to FEN1 loss was validated by studies showing that small-molecule FEN1 inhibitors and FEN1 small interfering RNAs (siRNAs) selectively killed BRCA1- and BRCA2-defective human cell lines. Furthermore, the differential sensitivity to FEN1 inhibition was recapitulated in mice, where a small-molecule FEN1 inhibitor reduced the growth of tumors established from drug-sensitive but not drug-resistant cancer cell lines. FEN1 inhibition induced a DNA damage response in both sensitive and resistant cell lines; however, sensitive cell lines were unable to recover and replicate DNA even when the inhibitor was removed. Although FEN1 inhibition activated caspase to higher levels in sensitive cells, this apoptotic response occurred in p53-defective cells and cell killing was not blocked by a pan-caspase inhibitor. These results suggest that FEN1 inhibitors have the potential for therapeutically targeting HR-defective cancers such as those resulting from BRCA1 and BRCA2 mutations, and other genetic defects.

Keywords:  DNA repair; DNA replication; cancer therapy; homologous recombination; synthetic lethality

DOI:  https://doi.org/10.1073/pnas.2009237117
Cancer Lett. 2020 Jul 28. pii: S0304-3835(20)30350-5. [Epub ahead of print]

Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer.

Cristina Nieto-Jiménez, Eva M Galan-Moya, Verónica Corrales-Sánchez, María Del Mar Noblejas-López, Miguel Burgos, Beatriz Domingo, Juan Carlos Montero, Mónica Gómez-Juárez, María Granada Picazo-Martínez, Azucena Esparis-Ogando, Atanasio Pandiella, Alberto Ocaña.

  The inhibition of bromo- and extraterminal domains (BET) has shown an anti-proliferative effect in triple negative breast cancer (TNBC). In this article we explore mechanisms of resistance to BET inhibitors (BETi) in TNBC, with the aim of identifying novel ways to overcome such resistance. Two cellular models of acquired resistance to the BET inhibitor JQ1 were generated using a pulsed treatment strategy. MTT, colony formation, and cytometry assays revealed that BETi-resistant cells were particularly sensitive to PLK1 inhibition. Targeting of the latter reduced cell proliferation, especially in resistant cultures. Quantitative PCR analysis of a panel of mitotic kinases uncovered an increased expression of AURKA, TTK, and PLK1, confirmed by Western blot. Only pharmacological inhibition of PLK1 showed anti-proliferative activity on resistant cells, provoking G2/M arrest, increasing expression levels of cyclin B, pH3 and phosphorylation of Bcl-2 proteins, changes that were accompanied by induction of caspase-dependent apoptosis. JQ1-resistant cells orthotopically xenografted into the mammary fat pad of mice led to tumours that retained JQ1-resistance. Administration of the PLK1 inhibitor volasertib resulted in tumour regression. These findings open avenues to explore the future use of PLK1 inhibitors in the clinical setting of BETi-resistant patients.

Keywords:  Cancer resistance; Caspase-dependent apoptotic cell death; Epigenetic; JQ1; Volasertib

DOI:  https://doi.org/10.1016/j.canlet.2020.06.020
Blood Adv. 2020 Jul 28. 4(14): 3316-3328

BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression.

Thomas E C Cummin, Kerry L Cox, Tom D Murray, Anna H Turaj, Lisa Dunning, Vikki L English, Rachel Fell, Graham Packham, Yan Ma, Ben Powell, Peter W M Johnson, Mark S Cragg, Matthew J Carter.

Although the MYC oncogenic network represents an attractive therapeutic target for lymphoma, MYC inhibitors have been difficult to develop. Alternatively, inhibitors of epigenetic/ transcriptional regulators, particularly the bromodomain and extraterminal (BET) family, have been used to modulate MYC. However, current benzodiazepine-derivative BET inhibitors (BETi) elicit disappointing responses and dose-limiting toxicity in relapsed/refractory lymphoma, potentially because of enrichment of high-risk molecular features and chemical backbone-associated toxicities. Consequently, novel nonbenzodiazepine BETi and improved mechanistic understanding are required. Here we characterize the responses of aggressive MYC-driven lymphomas to 2 nonbenzodiazepine BETi: PLX51107 and PLX2853. Both invoked BIM-dependent apoptosis and in vivo therapy, associated with miR-17∼92 repression, in murine Eµ-myc lymphomas, with PLX2853 exhibiting enhanced potency. Accordingly, exogenous BCL-2 expression abrogated these effects. Because high BCL-2 expression is common in diffuse large B-cell lymphoma (DLBCL), BETi were ineffective in driving apoptosis and in vivo therapy of DLBCL cell lines, mirroring clinical results. However, BETi-mediated BIM upregulation and miR-17∼92 repression remained intact. Consequently, coadministration of BETi and ABT199/venetoclax restored cell death and in vivo therapy. Collectively, these data identify BIM-dependent apoptosis as a critical mechanism of action for this class of BETi that, via coadministration of BH3 mimetics, can deliver effective tumor control in DLBCL.

DOI: https://doi.org/10.1182/bloodadvances.2020002231