bims-ectoca 2021-12-26 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2021‒12‒26
ten papers selected by
Ankita Daiya, Birla Institute of Technology and Science

HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases.
Role of HDAC6 and Its Selective Inhibitors in Gastrointestinal Cancer.
Small molecule targeting of chromatin writers in cancer.
Designing HDAC-PROTACs: lessons learned so far.
Imperatorin induces autophagy and G0/G1 phase arrest via PTEN-PI3K-AKT-mTOR/p21 signaling pathway in human osteosarcoma cells in vitro and in vivo.
Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer.
Context-dependent transcriptional regulations of YAP/TAZ in cancer.
KDM6 Demethylases and Their Roles in Human Cancers.
Mutual Modulation Between Extracellular Vesicles and Mechanoenvironment in Bone Tumors.
geoCancerPrognosticDatasetsRetriever, a bioinformatics tool to easily identify cancer prognostic datasets on Gene Expression Omnibus (GEO).

Transl Oncol. 2021 Dec 16. pii: S1936-5233(21)00303-X. [Epub ahead of print]16 101312

HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases.

Geetha Shanmugam, Sudeshna Rakshit, Koustav Sarkar.

  Histone deacetylases (HDACs) are enzymes that play a key role in the epigenetic regulation of gene expression by remodeling chromatin. Inhibition of HDACs is a prospective therapeutic approach for reversing epigenetic alteration in several diseases. In preclinical research, numerous types of HDAC inhibitors were discovered to exhibit powerful and selective anticancer properties. However, such research has revealed that the effects of HDAC inhibitors may be far broader and more intricate than previously thought. This review will provide insight into the HDAC inhibitors and their mechanism of action with special emphasis on the significance of HDAC inhibitors in the treatment of Chronic Obstructive Pulmonary Disease and lung cancer. Nanocarrier-mediated HDAC inhibitor delivery and new approaches for targeting HDACs are also discussed.

Keywords:  Chronic obstructive pulmonary disease; Epigenetic regulation; HDAC inhibitors; Histone deacetylases; Lung cancer; Nanocarrier-mediated HDAC inhibitor delivery

DOI:  https://doi.org/10.1016/j.tranon.2021.101312
Front Cell Dev Biol. 2021 ;9 719390

Role of HDAC6 and Its Selective Inhibitors in Gastrointestinal Cancer.

Bingyi Zhou, Deliang Liu, Yuyong Tan.

  Worldwide, cancer is the second leading cause of mortality after cardiovascular diseases. Among the numerous malignant tumors in human, digestive system cancers are the primary cause of morbidity and mortality. Acetylation and deacetylation are crucially involved in cancer occurrence and development; in addition, the deacetylation process is regulated by histone deacetylases (HDACs). Among the 18 human HDACs that have been reported, HDAC6 has been widely studied. There is upregulated HDAC6 expression in numerous types of tumor tissues and is closely associated with clinicopathological characteristics. Moreover, several HDAC6 inhibitors have been identified; furthermore, there has been extensive research on their ability to inhibit the growth of many tumors. This review summarizes the roles of HDAC6 in different primary digestive system malignancies.

Keywords:  deacetylation; gastrointestinal cancer; histone deacetylase inhibitor; histone deacetylases; ubiquitination

DOI:  https://doi.org/10.3389/fcell.2021.719390
Nat Chem Biol. 2021 Dec 24.

Small molecule targeting of chromatin writers in cancer.

Andrew R Conery, Jennifer L Rocnik, Patrick Trojer.

More than a decade after the launch of DNA methyltransferase and histone deacetylase inhibitors for the treatment of cancer, 2020 heralded the approval of the first histone methyltransferase inhibitor, revitalizing the concept that targeted manipulation of the chromatin regulatory landscape can have profound therapeutic impact. Three chromatin regulatory pathways-DNA methylation, histone acetylation and methylation-are frequently implicated in human cancer but hundreds of potentially druggable mechanisms complicate identification of key targets for therapeutic intervention. In addition to human genetics and functional screening, chemical biology approaches have proven critical for the discovery of key nodes in these pathways and in an ever-increasing complexity of molecularly defined human cancer contexts. This review introduces small molecule targeting approaches, showcases chemical probes and drug candidates for epigenetic writer enzymes, illustrates molecular features that may represent epigenetic dependencies and suggests translational strategies to maximize their impact in cancer therapy.

DOI: https://doi.org/10.1038/s41589-021-00920-5
Future Med Chem. 2021 Dec 24.

Designing HDAC-PROTACs: lessons learned so far.

Fabian Fischer, Leandro A Alves Avelar, Laoise Murray, Thomas Kurz.

  Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into Phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC-PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC-PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.

Keywords:  PROTAC; epigenetics; histone deacetylases; protein degradation; ubiquitin proteasome system

DOI:  https://doi.org/10.4155/fmc-2021-0206
Cancer Cell Int. 2021 Dec 19. 21(1): 689

Imperatorin induces autophagy and G0/G1 phase arrest via PTEN-PI3K-AKT-mTOR/p21 signaling pathway in human osteosarcoma cells in vitro and in vivo.

Minchao Lv, Qingxin Xu, Bei Zhang, Zhiqiang Yang, Jun Xie, Jinku Guo, Feixiong He, Wei Wang.

  BACKGROUND: Osteosarcoma is the third most common cancer in adolescence and the first common primary malignant tumor of bone. The long-term prognosis of osteosarcoma still remains unsatisfactory in the past decades. Therefore, development of novel therapeutic agents which are effective to osteosarcoma and are safe to normal tissue simultaneously is quite essential and urgent.METHODS: Firstly, MTT assay, cell colony formation assay, cell migration and invasion assays were conducted to evaluate the inhibitory effects of imperatorin towards human osteosarcoma cells. RNA-sequence assay and bioinformatic analysis were then performed to filtrate and assume the potential imperatorin-induced cell death route and signaling pathway. Moreover, quantitative real-time PCR assay, western blot assay and rescue experiments were conducted to confirm the assumptions of bioinformatic analysis. Finally, a subcutaneous tumor-transplanted nude mouse model was established and applied to evaluate the internal effect of imperatorin on osteosarcoma by HE and immunohistochemistry staining.
RESULTS: Imperatorin triggered time-dependent and dose-dependent inhibition of tumor growth mainly by inducing autophagy promotion and G0/G1 phase arrest in vitro and in vivo. Besides, imperatorin treatment elevated the expression level of PTEN and p21, down-regulated the phosphorylation of AKT and mTOR. In contrast, the inhibition of PTEN using Bpv (HOpic), a potential and selective inhibitor of PTEN, concurrently rescued imperatorin-induced autophagy promotion, cell cycle arrest and inactivation of PTEN-PI3K-AKT-mTOR/p21 pathway.
CONCLUSIONS: This work firstly revealed that imperatorin induced autophagy and cell cycle arrest through PTEN-PI3K-AKT-mTOR/p21 signaling pathway by targeting and up-regulating PTEN in human osteosarcoma cells. Hence, imperatorin is a desirable candidate for clinical treatments of osteosarcoma.

Keywords:  Autophagy; Cell cycle; Imperatorin; Osteosarcoma; PTEN-PI3K-AKT-mTOR/p21 pathway

DOI:  https://doi.org/10.1186/s12935-021-02397-7
Cells. 2021 Dec 08. pii: 3463. [Epub ahead of print]10(12):

Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer.

Shilpa Patil, Teresa Forster, Kristina Reutlinger, Waltraut Kopp, Lennart Versemann, Jessica Spitalieri, Jochen Gaedcke, Philipp Ströbel, Shiv K Singh, Volker Ellenrieder, Albrecht Neesse, Elisabeth Hessmann.

  BACKGROUND: The Nuclear Factor of Activated T-cells 1 (NFATc1) transcription factor and the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) significantly contribute to the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). Herein, we aimed at dissecting the mechanistic background of their interplay in PDAC progression.METHODS: NFATc1 and EZH2 mRNA and protein expression and complex formation were determined in transgenic PDAC models and human PDAC specimens. NFATc1 binding on the Ezh2 gene and the consequences of perturbed NFATc1 expression on Ezh2 transcription were explored by Chromatin Immunoprecipitation (ChIP) and upon transgenic or siRNA-mediated interference with NFATc1 expression, respectively. Integrative analyses of RNA- and ChIP-seq data was performed to explore NFATc1-/EZH2-dependent gene signatures.
RESULTS: NFATc1 targets the Ezh2 gene for transcriptional activation and biochemically interacts with the methyltransferase in murine and human PDAC. Surprisingly, our genome-wide binding and expression analyses do not link the protein complex to joint gene regulation. In contrast, our findings provide evidence for chromatin-independent functions of the NFATc1:EZH2 complex and reveal posttranslational EZH2 phosphorylation at serine 21 as a prerequisite for robust complex formation.
CONCLUSION: Our findings disclose a previously unknown NFATc1-EZH2 axis operational in the pancreas and provide mechanistic insights into the conditions fostering NFATc1:EZH2 complex formation in PDAC.

Keywords:  EZH2; NFATc1; chromatin; pancreatic cancer; posttranslational EZH2 modification

DOI:  https://doi.org/10.3390/cells10123463
Cancer Lett. 2021 Dec 21. pii: S0304-3835(21)00631-5. [Epub ahead of print]

Context-dependent transcriptional regulations of YAP/TAZ in cancer.

Yibo Guo, Juan Luo, Hailin Zou, Chenxin Liu, Liang Deng, Peng Li.

  As the downstream effectors of Hippo pathway, YAP/TAZ are identified to participate in organ growth, regeneration and tumorigenesis. However, owing to lack of a DNA-binding domain, YAP/TAZ usually act as coactivators and are dependent on other transcription factors to mediate their transcriptional outputs. In this review, we will first provide an overview on the core components of Hippo signalling and the upstream regulators of this pathway in mammals, and then systematically summarize the identified transcription factors or partners that are responsible for the downstream transcriptional output of YAP/TAZ in various cancers. More than that, we will discuss the potential applications and future directions based on these findings.

Keywords:  Context-dependent; Hippo signaling; Transcriptional output; YAP/TAZ

DOI:  https://doi.org/10.1016/j.canlet.2021.12.019
Front Oncol. 2021 ;11 779918

KDM6 Demethylases and Their Roles in Human Cancers.

Chunyan Hua, Jiaqing Chen, Shuting Li, Jianan Zhou, Jiahong Fu, Weijian Sun, Wenqian Wang.

  Cancer therapy is moving beyond traditional chemotherapy to include epigenetic approaches. KDM6 demethylases are dynamic regulation of gene expression by histone demethylation in response to diverse stimuli, and thus their dysregulation has been observed in various cancers. In this review, we first briefly introduce structural features of KDM6 subfamily, and then discuss the regulation of KDM6, which involves the coordinated control between cellular metabolism (intrinsic regulators) and tumor microenvironment (extrinsic stimuli). We further describe the aberrant functions of KDM6 in human cancers, acting as either a tumor suppressor or an oncoprotein in a context-dependent manner. Finally, we propose potential therapy of KDM6 enzymes based on their structural features, epigenetics, and immunomodulatory mechanisms, providing novel insights for prevention and treatment of cancers.

Keywords:  KDM6; cancer; cancer therapy; epigenetics; histone demethylase

DOI:  https://doi.org/10.3389/fonc.2021.779918
Front Cell Dev Biol. 2021 ;9 789674

Mutual Modulation Between Extracellular Vesicles and Mechanoenvironment in Bone Tumors.

Enrica Urciuoli, Barbara Peruzzi.

  The bone microenvironment homeostasis is guaranteed by the balanced and fine regulated bone matrix remodeling process. This equilibrium can be disrupted by cancer cells developed in the bone (primary bone cancers) or deriving from other tissues (bone metastatic lesions), through a mechanism by which they interfere with bone cells activities and alter the microenvironment both biochemically and mechanically. Among the factors secreted by cancer cells and by cancer-conditioned bone cells, extracellular vesicles (EVs) are described to exert pivotal roles in the establishment and the progression of bone cancers, by conveying tumorigenic signals targeting and transforming normal cells. Doing this, EVs are also responsible in modulating the production of proteins involved in regulating matrix stiffness and/or mechanotransduction process, thereby altering the bone mechanoenvironment. In turn, bone and cancer cells respond to deregulated matrix stiffness by modifying EV production and content, fueling the vicious cycle established in tumors. Here, we summarized the relationship between EVs and the mechanoenvironment during tumoral progression, with the final aim to provide some innovative perspectives in counteracting bone cancers.

Keywords:  bone tumors; extracellular vesicles; mechanoenvironment; metastatization; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2021.789674
Bioinformatics. 2021 Dec 22. pii: btab852. [Epub ahead of print]

geoCancerPrognosticDatasetsRetriever, a bioinformatics tool to easily identify cancer prognostic datasets on Gene Expression Omnibus (GEO).

Abbas Alameer, Davide Chicco.

SUMMARY: Having multiple datasets is a key aspect of robust bioinformatics analyses, because it allows researchers to find possible confirmation of the discoveries made on multiple cohorts. For this purpose, Gene Expression Omnibus (GEO) can be a useful database, since it provides hundreds of thousands of microarray gene expression datasets freely available for download and usage. Despite this large availability, collecting prognostic datasets of a specific cancer type from GEO can be a long, time-consuming, and energy-consuming activity for any bioinformatician, who needs to execute it manually by first performing a search on the GEO website and then by checking all the datasets found one by one. To solve this problem, we present here geoCancerPrognosticDatasetsRetriever, a Perl 5 application which reads a cancer type and a list of microarray platforms, searches for prognostic gene expression datasets of that cancer type and based on those platforms available on GEO, and returns the GEO accession codes of those datasets, if found. Our bioinformatics tool can easily generate in a few minutes a list of cancer prognostic datasets that otherwise would require numerous hours of manual work to any bioinformatician. geoCancerPrognosticDatasetsRetriever can handily retrieve multiple prognostic datasets of gene expression of any cancer type, laying the foundations for numerous bioinformatics studies and meta-analyses that can have a strong impact on oncology research.AVAILABILITY AND IMPLEMENTATION: geoCancerPrognosticDatasetsRetriever is freely available under the GPLv2 license on the Comprehensive Perl Archive Network (CPAN) at https://metacpan.org/pod/App::geoCancerPrognosticDatasetsRetriever and on GitHub at https://github.com/AbbasAlameer/geoCancerPrognosticDatasetsRetriever.

DOI: https://doi.org/10.1093/bioinformatics/btab852