bims-ectoca 2022-10-02 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–10–02
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies.
Bioinformatics Pipelines for Identification of Super-Enhancers and 3D Chromatin Contacts.
YAP Activates STAT3 Signalling to Promote Colonic Epithelial Cell Proliferation in DSS-Induced Colitis and Colitis Associated Cancer.
Prognostic analysis of Yes-associated protein 1 in patients with colorectal cancer. A systematic review and meta-analsysis.
Chromatin Immunoprecipitation Sequencing (ChIP-seq) for Detecting Histone Modifications and Modifiers.
Bisphenol A interacts with DLGAP5 and regulates IL-6/JAK2/STAT3 signaling pathway to promote tumorigenesis and progression of osteosarcoma.
Multi-targeted HDAC inhibitors as Anticancer Agents: Current Status and Future Prospective.

J Med Chem. 2022 Sep 25.

Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies.

Dehua Lu, Cheng Wang, Lailiang Qu, Fucheng Yin, Shang Li, Heng Luo, Yonglei Zhang, Xingchen Liu, Xinye Chen, Zhongwen Luo, Ningjie Cui, Lingyi Kong, Xiaobing Wang.

Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies. We designed HDAC and EZH2 dual inhibitors based on the strong synergistic effect of SAHA and GSK126. Compound 20 exhibited excellent inhibitory activity against HDAC1 (IC50 = 0.12 μM) and EZH2 (IC50 = 0.059 μM), it also showed good antiproliferation activity against MV4-11 (IC50 = 0.17 μM), which has more potential than the cocktail therapy of SAHA and GSK126 (IC50 = 0.40 μM). 20 suppressed tumor growth in vivo, which was as good as the combination therapy. These results suggested that 20 may be a promising drug candidate for treating hematological malignancies.

DOI: https://doi.org/10.1021/acs.jmedchem.2c00673
Methods Mol Biol. 2023 ;2577 123-146

Bioinformatics Pipelines for Identification of Super-Enhancers and 3D Chromatin Contacts.

Akihiko Sakashita, Chikara Takeuchi, So Maezawa, Satoshi H Namekawa.

  Precise regulation of gene expression is integral in development. Emerging studies have highlighted that super-enhancers (SEs), which are clusters of multiple enhancers, play critical roles in regulating cell type-specific gene expression via 3D chromatin, thereby defining the cellular identities of given cells. Here we provide optimized bioinformatics pipelines to identify SEs and 3D chromatin contacts. Our pipelines encompass the processing of chromatin immunoprecipitation sequencing (ChIP-seq) data to identify SEs and the processing of genome-wide chromosome conformation capture (Hi-C) data. We can then infer long-range chromatin contacts between SEs and other genomic regions. This integrative computational approach, which can be applied to CUT&RUN and CUT&Tag, alternative technologies to ChIP-seq, allows us to identify genomic locations of SEs and their 3D genome configuration, whereby multiple SEs act in concert. We show an analysis of mouse spermatogenesis as an example of this application.

Keywords:  ChIP-seq; Chromatin contact; Enhancer; Gene regulation; Hi-C; Meiosis; Promoter–enhancer interaction; Spermatogenesis; Super-enhancer; Transcription factor-binding

DOI:  https://doi.org/10.1007/978-1-0716-2724-2_9
J Inflamm Res. 2022 ;15 5471-5482

YAP Activates STAT3 Signalling to Promote Colonic Epithelial Cell Proliferation in DSS-Induced Colitis and Colitis Associated Cancer.

Feihong Deng, Zengrong Wu, Mengmeng Xu, Pianpian Xia.

   Background and Aims: Yes-associated protein (YAP) is a key transcriptional coactivator of cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in colonic epithelial regeneration and tumourigenesis.
Methods: Murine DSS-induced colitis and YAP overexpression models were constructed via lentiviral intraperitoneal injection. Stable YAP-overexpressing cells, protein immunoprecipitation, and ChIP were used to deeply explore the molecular mechanism.
Results: We found that the expression of YAP was dramatically diminished in the colonic crypts during the acute colitis phase, while YAP was strikingly enhanced to initiate tissue repair after DSS withdrawal. Overexpressing YAP in mice drastically accelerated epithelial regeneration, presenting with more intact structural integrity and reduced inflammatory cell infiltration in the mucosa. Further mechanistic studies showed that the expression of YAP in the nucleus was significantly increased by 2 h post-DSS removal, accompanied by upregulated protein levels of activated STAT3. Overexpression of YAP (YAPWT) elevated the expression of activated STAT3 and its transcriptional targets and strengthened the proliferation and "wound healing" ability of colonic cells. However, these effects were reversed when STAT3 was silenced in YAPWT cells. Moreover, YAP could directly interact with STAT3 in the nucleus, and c-Myc and CyclinD1 were the transcriptional targets. Finally, during colitis-associated cancer (CAC), YAPWT promoted the progression of CAC, while the phosphomimetic YAP downregulated the expression of STAT3 and inhibited the development and progression of CAC.
Conclusion: YAP activates STAT3 signalling to facilitate mucosal regeneration after DSS-induced colitis. However, excessive YAP activation in the colonic epithelium promotes CAC development.

Keywords:  DSS induced colitis; STAT3; YAP; colitis-associated cancer; dextran sodium sulfate; mucosal repair

DOI:  https://doi.org/10.2147/JIR.S377077
Rev Esp Enferm Dig. 2022 Sep 30.

Prognostic analysis of Yes-associated protein 1 in patients with colorectal cancer. A systematic review and meta-analsysis.

Hui Zhang, Mengqi Yin, Yu Hu, Mingming Jiang, Mingliang Lu, Yajuan Wu.

   BACKGROUND: Colorectal cancer (CRC) is the most common carcinoma worldwide, but a lack of effective prognostic markers limits the clinical diagnosis and treatment. Yes-associated protein 1 (YAP1) is an effector of the HIPPO-pathway, which plays a critical role in cancer development and prognosis, including CRC. However, previous reports have suggested that it plays a dual role in CRC.
METHODS: A meta-analysis using RevMan software 5.4 and Stata 14.0 was performed to evaluate the relationship between YAP1 and clinical outcomes of CRC, after searching for eligible studies from the PubMed, Web of Science and Embase databases. Online datasets GEPIA and LOGpc were also used to calculate survival results and compare with the meta-analysis results. Besides, "DESeq" packages was used for expression analysis of YAP1 from TCGA dataset.
RESULTS: YAP1 was over expression in the tissue of cancers comparing to normal tissues in patients with CRC from TCGA database (p=0.000164) and GEPIA database. A total of 10 studies involving 2305 patients from literatures were selected. Pooled HR indicated that over-expression of YAP1 was associated with poor clinical outcomes (HR=1.70, 95% CI: 1.28-2.26, p=0.0003). Subgroup analysis showed a clear correlation between over-expression of YAP1 and worse survival rate in Chinese patients (HR=1.94, 95% CI: 1.40-2.69, p=0.0001), nuclear YAP1 over-expression (HR=2.07, 95% CI: 1.29-3.31, p=0.003), 60 months follow-up duration (HR=1.89, 95% CI: 1.30-2.73, p=0.0008), IHC test (HR=1.65, 95% CI: 1.17-2.33, p=0.005), IHC combined with other tests (HR=1.77, 95% CI: 1.13-2.77, p=0.01) and multivariate analysis (HR=1.70, 95% CI: 1.24-2.31, p=0.0009). Nevertheless, disease-free survival (DFS) did not show significant result in the patients with CRC in our meta-analysis (HR=1.38, 95% CI: 0.51-3.75, p=0.52) as well as in the GEPIA and LOGpc databases. Meanwhile, YAP1 over-expression was also significantly associated with worse overall survival (OS) in GSE17536, GSE40967, GSE29623 and GSE71187.
CONCLUSION: YAP1 over-expression is common in CRC tissues. Over-expression of YAP1 in CRC patients, particularly in the nucleus, might be related to shorter OS, maybe in the early stages. YAP1 could serve as a potential predictor of poor prognosis in CRC.

Keywords:  YAP1; colorectal cancer; meta-analysis online databases.; prognosis

DOI:  https://doi.org/10.17235/reed.2022.8472/2021
Methods Mol Biol. 2023 ;2577 55-64

Chromatin Immunoprecipitation Sequencing (ChIP-seq) for Detecting Histone Modifications and Modifiers.

Shinjiro Hino, Tetsuya Sato, Mitsuyoshi Nakao.

  Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is the most widely used method for analyzing genome-wide DNA-protein interactions. Because there is considerable variation in the modes and strengths of DNA-protein interactions, chromatin immunoprecipitation (ChIP) protocols have been diversified and optimized for different needs. Here, we describe protocols for detecting histone modifications and modifiers using various crosslinking and immunoprecipitation conditions. We provide a complete ChIP-seq workflow covering sample preparation, immunoprecipitation, next-generation sequencing (NGS) library preparation, and data analyses.

Keywords:  Dual crosslink; Histone; Immunoprecipitation; Next-generation sequencing

DOI:  https://doi.org/10.1007/978-1-0716-2724-2_4
Chemosphere. 2022 Sep 22. pii: S0045-6535(22)03038-7. [Epub ahead of print] 136545

Bisphenol A interacts with DLGAP5 and regulates IL-6/JAK2/STAT3 signaling pathway to promote tumorigenesis and progression of osteosarcoma.

Yanjun Wang, Yongfeng Yao, Keyvan Ramezani, Moein Bonakdar, Niusha Moghimi, Maryam Salimi, Kai Wang.

   OBJECTIVE: It has been suggested that Bisphenol A (BPA), a high-production-volume industrial chemical, can accelerate the development of various type of cancers. However, the effect of BPA on osteosarcoma and the underlying mechanisms are yet to be established. Therefore, in this study we tried to explore the carcinogenic effects of BPA on osteosarcoma and the underlying mechanism.
METHODS: SaOs-2 cancer cell line was used to treat with BPA at the doses of 0.1, 1, 10 μM DGLAP5 knockdown and overexpression methods were constructed by using adenovirus mediated transfection, and the functional analysis of DGLAP5 was investigated to evaluate the carcinogenic effect of BPA on osteosarcoma through DLGAP5. Xenograft and metastatic mouse model were used to evaluate in vivo experiments.
RESULTS: In this study, BPA at 10 μM promoted the proliferation, migration and invasion in vitro, and accelerate the progression and metastasis in vivo. Also, exposure to BPA was associated with poor survival of osteosarcoma in mice. In addition, we observed that BPA at 10 μM significantly increased the expression of DGLAP5 in osteosarcoma. Silencing DGLAP5 could reverse the effect of BPA on proliferation, migration and invasion. Mechanically, BPA promoted IL-6, JAK2, and STAT3 expression and promoted tumor progression in an IL-6-dependent manner through up-regulation of DLGAP5.
CONCLUSION: Our findings demonstrated that BPA could promote the proliferation, migration, invasion of osteosarcoma cells and related to poor survival in a mouse model. DLGAP5 is one of the most critical targets of BPA to act as a carcinogen through IL-6/JAK2/STAT3 signaling pathway.

Keywords:  Discs large homolog associated protein 5; IL-6/JAK2/STAT3 signaling pathway; Osteosarcoma

DOI:  https://doi.org/10.1016/j.chemosphere.2022.136545
Curr Med Chem. 2022 Sep 22.

Multi-targeted HDAC inhibitors as Anticancer Agents: Current Status and Future Prospective.

Vijay K Patel, Ekta Shirbhate, Priya Tiwari, Rakesh Kore, Ravichandran Veerasamy, Achal Mishra, Harish Rajak.

  Multi-targeted agents can interact with multiple targets sequentially, resulting in synergistic and more effective therapies for several complicated disorders, including cancer, even with relatively modest activity. Histone deacetylase (HDAC) inhibitors are low molecular weight small compounds that increase the acetylation of histone and non-histone proteins, altering gene expression and thereby impacting angiogenesis, metastasis, and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular pathways thus produce adverse issues, causing therapeutic resistance and they have poor pharmacokinetic properties. The designing of HDAC based dual/multi-target inhibitor is an important strategy to overcome adverse effects, drug resistance and increase the effectiveness in controlling cancer. The selection of target combinations to design multitarget HDACinhibitor is generally accomplished on the basis of systematic high-throughput screening (HTS), network pharmacology analysis methods. The identification of the pharmacophore against individual targets is performed using rational or computation methods. The identified pharmacophore can combine with merged, fused, linked with the cleavable or non-cleavable linker to retain the interaction with the original target while being compatible with the other target.The objective of this review is to elucidate the designing strategies of the potential targets along with biological activity and recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents.This review elucidate the designing strategies of the potential target along with biological activity and recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. The development of HDAC-based dual/multi-target inhibitors is an important approach for overcoming side effects, drug resistance, and effective cancer control.

Keywords:  Anticancer; Computational methods; Designing strategies; Dual/multi-targeting; HDAC inhibitor; Histone deacetylase; Recent development.

DOI:  https://doi.org/10.2174/0929867329666220922105615