bims-ectoca 2022-01-09 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022‒01‒09
nine papers selected by
Ankita Daiya
BITS Pilani

Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights.
Design and synthesis of dual inhibitors targeting snail and histone deacetylase for the treatment of solid tumour cancer.
Computational modeling of chromatin accessibility identified important epigenomic regulators.
The importance of enhancer methylation for epigenetic regulation of tumorigenesis in squamous lung cancer.
LncRNA HCG18 promotes osteosarcoma growth by enhanced aerobic glycolysis via the miR-365a-3p/PGK1 axis.
Yes-associated protein reacts differently in vascular smooth muscle cells under different intensities of mechanical stretch.
Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain.
In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations.
Deformation of the nucleus by TGFβ1 via the remodeling of nuclear envelope and histone isoforms.

Clin Epigenetics. 2022 Jan 07. 14(1): 5

Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights.

Melanie R Müller, Aaron Burmeister, Margaretha A Skowron, Alexa Stephan, Felix Bremmer, Gamal A Wakileh, Patrick Petzsch, Karl Köhrer, Peter Albers, Daniel Nettersheim.

  BACKGROUND: Type II germ cell tumors (GCT) are the most common solid cancers in males of age 15 to 35 years. Treatment of these tumors includes cisplatin-based therapy achieving high cure rates, but also leading to late toxicities. As mainly young men are suffering from GCTs, late toxicities play a major role regarding life expectancy, and the development of therapy resistance emphasizes the need for alternative therapeutic options. GCTs are highly susceptible to interference with the epigenetic landscape; therefore, this study focuses on screening of drugs against epigenetic factors as a treatment option for GCTs.RESULTS: We present seven different epigenetic inhibitors efficiently decreasing cell viability in GCT cell lines including cisplatin-resistant subclones at low concentrations by targeting epigenetic modifiers and interactors, like histone deacetylases (Quisinostat), histone demethylases (JIB-04), histone methyltransferases (Chaetocin), epigenetic readers (MZ-1, LP99) and polycomb-repressive complexes (PRT4165, GSK343). Mass spectrometry-based analyses of the histone modification landscape revealed effects beyond the expected mode-of-action of each drug, suggesting a wider spectrum of activity than initially assumed. Moreover, we characterized the effects of each drug on the transcriptome of GCT cells by RNA sequencing and found common deregulations in gene expression of ion transporters and DNA-binding factors. A kinase array revealed deregulations of signaling pathways, like cAMP, JAK-STAT and WNT.
CONCLUSION: Our study identified seven drugs against epigenetic modifiers to treat cisplatin-resistant GCTs. Further, we extensively analyzed off-target effects and modes-of-action, which are important for risk assessment of the individual drugs.

Keywords:  Epi-drugs; Epigenetic modifier; Epigenetics; Germ cell tumor; Histone deacetylase inhibitor; Histone demethylase inhibitor; Histone methyltransferase inhibitor; Histone modification; PROTAC; Therapy

DOI:  https://doi.org/10.1186/s13148-021-01223-1
Eur J Med Chem. 2021 Dec 30. pii: S0223-5234(21)00931-4. [Epub ahead of print]229 114082

Design and synthesis of dual inhibitors targeting snail and histone deacetylase for the treatment of solid tumour cancer.

Hao Cui, Jingkun Huang, Yan Lei, Quanwei Chen, Zan Hu, Jiaqi Niu, Ran Wei, Kang Yang, Hongmei Li, Tao Lu, Yong Zhu, Yatian Huang.

  Snail and histone deacetylases (HDACs) have an important impact on cancer treatment, especially for their synergy. Therefore, the development of inhibitors targeting both Snail and HDAC might be a promising strategy for the treatment of cancers. In this work, we synthesized a series of Snail/HDAC dual inhibitors. Compound 9n displayed the most potent inhibitory activity against HDAC1 with an IC50 of 0.405 μM, potent inhibition against Snail with a Kd of 0.180 μM, and antiproliferative activity in HCT-116 cell lines with an IC50 of 0.0751 μM. Compound 9n showed a good inhibitory effect on NCI-H522 (GI50 = 0.0488 μM), MDA-MB-435 (GI50 = 0.0361 μM), and MCF7 (GI50 = 0.0518 μM). Docking studies showed that compound 9n can be well docked into the active binding sites of Snail and HDAC. Further studies showed that compound 9n increased histone H4 acetylation in HCT-116 cells and decreased the expression of Snail protein to induce cell apoptosis. These findings highlight the potential for the development of Snail/HDAC dual inhibitors as anti-solid tumour cancer drugs.

Keywords:  Antiproliferative; Dual; HCT-116; HDACs; Snail

DOI:  https://doi.org/10.1016/j.ejmech.2021.114082
BMC Genomics. 2022 Jan 08. 23(1): 19

Computational modeling of chromatin accessibility identified important epigenomic regulators.

Yanding Zhao, Yadong Dong, Wei Hong, Chongming Jiang, Kevin Yao, Chao Cheng.

  Chromatin accessibility is essential for transcriptional activation of genomic regions. It is well established that transcription factors (TFs) and histone modifications (HMs) play critical roles in chromatin accessibility regulation. However, there is a lack of studies that quantify these relationships. Here we constructed a two-layer model to predict chromatin accessibility by integrating DNA sequence, TF binding, and HM signals. By applying the model to two human cell lines (GM12878 and HepG2), we found that DNA sequences had limited power for accessibility prediction, while both TF binding and HM signals predicted chromatin accessibility with high accuracy. According to the HM model, HM features determined chromatin accessibility in a cell line shared manner, with the prediction power attributing to five core HM types. Results from the TF model indicated that chromatin accessibility was determined by a subset of informative TFs including both cell line-specific and generic TFs. The combined model of both TF and HM signals did not further improve the prediction accuracy, indicating that they provide redundant information in terms of chromatin accessibility prediction. The TFs and HM models can also distinguish the chromatin accessibility of proximal versus distal transcription start sites with high accuracy.

Keywords:  Chromatin accessibility; ENCODE; Histone modifications; Machine learning; Transcription factor

DOI:  https://doi.org/10.1186/s12864-021-08234-5
Exp Mol Med. 2022 Jan 05.

The importance of enhancer methylation for epigenetic regulation of tumorigenesis in squamous lung cancer.

Jae-Won Cho, Hyo Sup Shim, Chang Young Lee, Seong Yong Park, Min Hee Hong, Insuk Lee, Hye Ryun Kim.

Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer (NSCLC). LUSC occurs at the bronchi, shows a squamous appearance, and often occurs in smokers. To determine the epigenetic regulatory mechanisms of tumorigenesis, we performed a genome-wide analysis of DNA methylation in tumor and adjacent normal tissues from LUSC patients. With the Infinium Methylation EPIC Array, > 850,000 CpG sites, including ~350,000 CpG sites for enhancer regions, were profiled, and the differentially methylated regions (DMRs) overlapping promoters (pDMRs) and enhancers (eDMRs) between tumor and normal tissues were identified. Dimension reduction based on DMR profiles revealed that eDMRs alone and not pDMRs alone can differentiate tumors from normal tissues with the equivalent performance of total DMRs. We observed a stronger negative correlation of LUSC-specific gene expression with methylation for enhancers than promoters. Target genes of eDMRs rather than pDMRs were found to be enriched for tumor-associated genes and pathways. Furthermore, DMR methylation associated with immune infiltration was more frequently observed among enhancers than promoters. Our results suggest that methylation of enhancer regions rather than promoters play more important roles in epigenetic regulation of tumorigenesis and immune infiltration in LUSC.

DOI: https://doi.org/10.1038/s12276-021-00718-4
Cell Mol Biol Lett. 2022 Jan 06. 27(1): 5

LncRNA HCG18 promotes osteosarcoma growth by enhanced aerobic glycolysis via the miR-365a-3p/PGK1 axis.

Xiaohui Pan, Jin Guo, Canjun Liu, Zhanpeng Pan, Zhicheng Yang, Xiang Yao, Jishan Yuan.

  BACKGROUND: Osteosarcoma (OS) is a common primary bone malignancy. Long noncoding RNA HCG18 is known to play an important role in a variety of cancers. However, its role in OS and relevant molecular mechanisms are unclear.METHODS: Real-time quantitative PCR was performed to determine the expression of target genes. Function experiments showed the effects of HCG18 and miR-365a-3p on OS cell growth.
RESULTS: HCG18 expression was increased in OS cell lines. Moreover, in vitro and in vivo experiments demonstrated that HCG18 knockdown inhibited OS cell proliferation. Mechanistically, HCG18 was defined as a competing endogenous RNA by sponging miR-365a-3p, thus elevating phosphoglycerate kinase 1 (PGK1) expression by directly targeting its 3'UTR to increase aerobic glycolysis.
CONCLUSION: HCG18 promoted OS cell proliferation via enhancing aerobic glycolysis by regulating the miR-365a-3p/PGK1 axis. Therefore, HCG18 may be a potential target for OS treatment.

Keywords:  Aerobic glycolysis; HCG18; Osteosarcoma; PGK1; miR-365a-3p

DOI:  https://doi.org/10.1186/s11658-021-00304-6
Aging (Albany NY). 2022 Jan 04. 13(undefined):

Yes-associated protein reacts differently in vascular smooth muscle cells under different intensities of mechanical stretch.

Xinhao Wang, Xiangdang Liang, Lujun Zhou, Shen Liu, Zhuoqun Fang, Chuanzhong Hu, Yigong Hou, Zhanshe Guo.

  Vascular smooth muscle cells (VSMCs) are stromal cells of the vascular wall and are continually exposed to mechanical signals. The loss of VSMCs is closely related to the occurrence of many vascular diseases, such as aortic aneurysms and aortic dissection. The proliferation and apoptosis of VSMCs are mechanically stimulated. Yes-associated protein (YAP), one of the core components of the Hippo pathway, plays a key role in the response of VSMCs to mechanical signals. In this study, we tested the impact of different intensities of mechanical stretch on the proliferation and apoptosis of VSMCs, as well as YAP. We tested VSMCs' proliferation and apoptosis and YAP reaction via immunocytochemistry, western blotting, CCK-8 and flow cytometric analysis. We found that 10% elongation could increase the phosphorylation of YAP and prevent it from entering the nucleus, as well as inhibit cell proliferation and promote apoptosis. However, 15% elongation reduced YAP phosphorylation and promoted its nuclear entry, thereby promoting cell proliferation and inhibiting apoptosis. Accordingly, YAP knockdown suppressed the phenotype of VMSCs induced by 15% elongation. Taken together, YAP regulates proliferation and apoptosis of VSMCs differently under different intensity of mechanical stretch. Mechanical stretch with appropriate intensity can promote the proliferation and inhibit apoptosis of VSMCs by activating YAP.

Keywords:  Hippo pathway; YAP; apoptosis; mechanical stretch; proliferation

DOI:  https://doi.org/10.18632/aging.203768
PLoS Genet. 2022 Jan 04. 18(1): e1009615

Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain.

Daniela Torres-Campana, Béatrice Horard, Sandrine Denaud, Gérard Benoit, Benjamin Loppin, Guillermo A Orsi.

The formation of a diploid zygote is a highly complex cellular process that is entirely controlled by maternal gene products stored in the egg cytoplasm. This highly specialized transcriptional program is tightly controlled at the chromatin level in the female germline. As an extreme case in point, the massive and specific ovarian expression of the essential thioredoxin Deadhead (DHD) is critically regulated in Drosophila by the histone demethylase Lid and its partner, the histone deacetylase complex Sin3A/Rpd3, via yet unknown mechanisms. Here, we identified Snr1 and Mod(mdg4) as essential for dhd expression and investigated how these epigenomic effectors act with Lid and Sin3A to hyperactivate dhd. Using Cut&Run chromatin profiling with a dedicated data analysis procedure, we found that dhd is intriguingly embedded in an H3K27me3/H3K9me3-enriched mini-domain flanked by DNA regulatory elements, including a dhd promoter-proximal element essential for its expression. Surprisingly, Lid, Sin3a, Snr1 and Mod(mdg4) impact H3K27me3 and this regulatory element in distinct manners. However, we show that these effectors activate dhd independently of H3K27me3/H3K9me3, and that dhd remains silent in the absence of these marks. Together, our study demonstrates an atypical and critical role for chromatin regulators Lid, Sin3A, Snr1 and Mod(mdg4) to trigger tissue-specific hyperactivation within a unique heterochromatin mini-domain.

DOI: https://doi.org/10.1371/journal.pgen.1009615
Turk J Pharm Sci. 2021 Dec 31. 18(6): 730-737

In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations.

Suat Sarı, Ahmet Avci, Ebru Koçak Aslan.

  Objectives: Drug repurposing is a highly popular approach to find new indications for drugs, which greatly reduces time and costs for drug design and discovery. Non-selective inhibitors of histone deacetylase (HDAC) isoforms including sirtuins (SIRTs) are effective against conditions like cancer. In this study, we used molecular docking to screen Food and Drug Administration (FDA)-approved drugs to identify a number of drugs with a potential to be repurposed for pan-HDAC and pan-SIRT inhibitor activity.Materials and Methods: The library of FDA-approved drugs was optimized using MacroModel. The crystal structures of HDAC1-4, 6-8, SIRT1-3, 5, 6 were prepared before the library was docked to each structure using Glide, FRED, and AutoDock Vina/PyRx. Consensus scores were derived from the docking scores obtained from each software. Pharmacophore modeling was performed using Phase.
Results: Based on the consensus scores, belinostat, bexarotene, and cianidanol emerged as top virtual pan-HDAC inhibitors whereas alosetron, cinacalcet, and indacaterol emerged as virtual pan-SIRT inhibitors. Pharmacophore hypotheses for these virtual inhibitors were also suggested through pharmacophore modeling in agreement with the molecular docking models.
Conclusion: The consensus approach enabled selection of the best performing drug molecules according to different software, and good scores against isoforms (virtual pan-HDAC and pan-SIRT inhibitors). The study not only proposes potential drugs to be repurposed for HDAC and SIRT-related diseases but also provides insights for designing potent de novo derivatives.

Keywords:  Drug repurposing; HDAC; consensus scoring; pharmacophore modeling; sirtuin; virtual screening

DOI:  https://doi.org/10.4274/tjps.galenos.2021.25564
Epigenetics Chromatin. 2022 Jan 04. 15(1): 1

Deformation of the nucleus by TGFβ1 via the remodeling of nuclear envelope and histone isoforms.

Ya-Hui Chi, Wan-Ping Wang, Ming-Chun Hung, Gunn-Guang Liou, Jing-Ya Wang, Pen-Hsiu Grace Chao.

  The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFβ1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFβ1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, clustering at the nuclear periphery and reintegrating into the nucleoplasm. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFβ1-induced compositional changes in the chromatin and nuclear lamina.

Keywords:  Nuclear envelope; Nuclear lamina; Nuclear morphology; TGFβ1

DOI:  https://doi.org/10.1186/s13072-021-00434-3