bims-ectoca 2021-12-12 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2021–12–12
fiveteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Histone 3 Lysine 27 Trimethylation Signature in Breast Cancer.
DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events.
Histone H3 lysine-trimethylation markers are decreased by recombinant methioninase and increased by methotrexate at concentrations which inhibit methionine-addicted osteosarcoma cell proliferation.
Mechanisms Underlying Hox-Mediated Transcriptional Outcomes.
Recent advances of SIRT1 and implications in chemotherapeutics resistance in cancer.
Mapping histone modification-dependent protein interactions with chemical proteomics.
Expression of histone deacetylase (HDAC) family members in bortezomib-refractory multiple myeloma and modulation by panobinostat.
Computational Prediction of lncRNA-Protein Interactions using Machine learning.
Tracking the Dynamic Histone Methylation of H3K27 in Live Cancer Cells.
Acetylation in Tumor Immune Evasion Regulation.
A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver.
Autophagy-Induced HDAC6 Activity During Hypoxia Regulates Mitochondrial Energy Metabolism Through the β-Catenin/COUP-TFII Axis in Hepatocellular Carcinoma Cells.
Peiminine Induces G0/G1-Phase Arrest, Apoptosis, and Autophagy via the ROS/JNK Signaling Pathway in Human Osteosarcoma Cells in Vitro and in Vivo.
Constructing gene regulatory networks using epigenetic data.
Amide-derived lysine analogues as substrates and inhibitors of histone lysine methyltransferases and acetyltransferases.

Int J Mol Sci. 2021 Nov 27. pii: 12853. [Epub ahead of print]22(23):

Histone 3 Lysine 27 Trimethylation Signature in Breast Cancer.

Lidia Borkiewicz.

  Cancer development and progression rely on complicated genetic and also epigenetic changes which regulate gene expression without altering the DNA sequence. Epigenetic mechanisms such as DNA methylation, histone modifications, and regulation by lncRNAs alter protein expression by either promoting gene transcription or repressing it. The presence of so-called chromatin modification marks at various gene promoters and gene bodies is associated with normal cell development but also with tumorigenesis and progression of different types of cancer, including the most frequently diagnosed breast cancer. This review is focused on the significance of one of the abundant post-translational modifications of histone 3- trimethylation of lysine 27 (H3K27me3), which was shown to participate in tumour suppressor genes' silencing. Unlike other reviews in the field, here the overview of existing evidence linking H3K27me3 status with breast cancer biology and the tumour outcome is presented especially in the context of diverse breast cancer subtypes. Moreover, the potential of agents that target H3K27me3 for the treatment of this complex disease as well as H3K27 methylation in cross-talk with other chromatin modifications and lncRNAs are discussed.

Keywords:  chromatin modification; gene silencing; histone methylation; histone post-translational modifications; transcriptional regulation

DOI:  https://doi.org/10.3390/ijms222312853
Nucleic Acids Res. 2021 Dec 06. pii: gkab1167. [Epub ahead of print]

DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events.

Richard Heery, Martin H Schaefer.

While large-scale studies applying various statistical approaches have identified hundreds of mutated driver genes across various cancer types, the contribution of epigenetic changes to cancer remains more enigmatic. This is partly due to the fact that certain regions of the cancer genome, due to their genomic and epigenomic properties, are more prone to dysregulated DNA methylation than others. Thus, it has been difficult to distinguish which promoter methylation changes are really driving carcinogenesis from those that are mostly just a reflection of their genomic location. By developing a novel method that corrects for epigenetic covariates, we reveal a small, concise set of potential epigenetic driver events. Interestingly, those changes suggest different modes of epigenetic carcinogenesis: first, we observe recurrent inactivation of known cancer genes across tumour types suggesting a higher convergence on common tumour suppressor pathways than previously anticipated. Second, in prostate cancer, a cancer type with few recurrently mutated genes, we demonstrate how the epigenome primes tumours towards higher tolerance of other aberrations.

DOI: https://doi.org/10.1093/nar/gkab1167
Biochem Biophys Rep. 2021 Dec;28 101177

Histone H3 lysine-trimethylation markers are decreased by recombinant methioninase and increased by methotrexate at concentrations which inhibit methionine-addicted osteosarcoma cell proliferation.

Yusuke Aoki, Yasunori Tome, Qinghong Han, Jun Yamamoto, Kazuyuki Hamada, Noriyuki Masaki, Michael Bouvet, Kotaro Nishida, Robert M Hoffman.

  Methionine addiction is a fundamental and general hallmark of cancer cells, which require exogenous methionine, despite their ability to synthesize normal amounts of methionine from homocysteine. In contrast, methionine-independent normal cells do not require exogenous methionine in the presence of a methionine precursor. The methionine addiction of cancer cells is due to excess transmethylation reactions. We have previously shown that histone H3 lysine marks are over-methylated in cancer cells and the over-methylation is unstable when the cancer cells are restricted of methionine. In the present study, we show that methionine-addicted osteosarcoma cells are sensitive to both methotrexate (MTX) and recombinant methioninase (rMETase), but they affect histone H3 lysine-methylation in the opposite direction. Concentrations of MTX and rMETase, which inhibit osteosarcoma cells viability to 20%, had opposing effects on the status of histone methylation of H3K9me3 and H3K27me3. rMETase significantly decreased the amount of H3K9me3 and H3K27me3. In contrast, MTX significantly increased the amount of H3K9me and H3K27me3. The results suggest that increase or decrease in these methylated histone lysine marks is associated with proliferation arrest of methionine-addicted osteosarcoma.

Keywords:  H3K27me3; H3K9me3; Histone; Methionine restriction; Methotrexate; Methylation; Osteosarcoma; Recombinant methioninase

DOI:  https://doi.org/10.1016/j.bbrep.2021.101177
Front Cell Dev Biol. 2021 ;9 787339

Mechanisms Underlying Hox-Mediated Transcriptional Outcomes.

Brittany Cain, Brian Gebelein.

  Metazoans differentially express multiple Hox transcription factors to specify diverse cell fates along the developing anterior-posterior axis. Two challenges arise when trying to understand how the Hox transcription factors regulate the required target genes for morphogenesis: First, how does each Hox factor differ from one another to accurately activate and repress target genes required for the formation of distinct segment and regional identities? Second, how can a Hox factor that is broadly expressed in many tissues within a segment impact the development of specific organs by regulating target genes in a cell type-specific manner? In this review, we highlight how recent genomic, interactome, and cis-regulatory studies are providing new insights into answering these two questions. Collectively, these studies suggest that Hox factors may differentially modify the chromatin of gene targets as well as utilize numerous interactions with additional co-activators, co-repressors, and sequence-specific transcription factors to achieve accurate segment and cell type-specific transcriptional outcomes.

Keywords:  Hox; chromatin accessibility; cis-regulatory modules (CRMs); protein-protein interaction; transcription factor

DOI:  https://doi.org/10.3389/fcell.2021.787339
Am J Cancer Res. 2021 ;11(11): 5233-5248

Recent advances of SIRT1 and implications in chemotherapeutics resistance in cancer.

Neelum Aziz Yousafzai, Hongchuan Jin, Mujib Ullah, Xian Wang.

Cancer is a big group of diseases and one of the leading causes of mortality worldwide. Despite enormous studies and efforts are being carried out in understanding the cancer and developing drugs against tumorigenesis, drug resistance is the main obstacle in cancer treatments. Chemotherapeutic treatment is an important part of cancer treatment and drug resistance is getting gradually multidimensional with the advancement of studies in cancer. The underlying mechanisms of drug resistance are largely unknown. Sirtuin1 (SIRT1) is a type of the Class III histone deacetylase family that is distinctively dependent on nicotinamide adenine dinucleotide (NAD+) for catalysis reaction. SIRT1 is a molecule which upon upregulation directly influences tumor progression, metastasis, tumor cell apoptosis, autophagy, DNA repair, as well as other interlinked tumorigenesis mechanism. It is involved in drug metabolism, apoptosis, DNA damage, DNA repair, and autophagy, which are key hallmarks of drug resistance and may contribute to multidrug resistance. Thus, understanding the role of SIRT1 in drug resistance could be important. This study focuses on the SIRT1 based mechanisms that might be a potential underlying approach in the development of cancer drug resistance and could be a potential target for drug development.

Keywords: DNA damage repair; SIRT1; chemotherapeutics resistance; tumorigenesis
Trends Biochem Sci. 2021 Dec 03. pii: S0968-0004(21)00241-3. [Epub ahead of print]

Mapping histone modification-dependent protein interactions with chemical proteomics.

Yanmei Chen, Yi Wang.

  Post-translational modifications (PTMs) of histones play essential roles in chromatin function and epigenetic regulation. Determining the interaction partners of these modifications is crucial to understanding transcriptional processes related to diverse developmental and pathological cues. We discuss how chemical proteomics can be applied to the simultaneous and global exploration of these interaction networks.

Keywords:  crosslink; disease; epigenetic; phosphorylation; protein–protein interactions; proximity biotinylation

DOI:  https://doi.org/10.1016/j.tibs.2021.11.002
Cancer Drug Resist. 2021 ;4(4): 888-902

Expression of histone deacetylase (HDAC) family members in bortezomib-refractory multiple myeloma and modulation by panobinostat.

Tiewei Cheng, Kendall Kiser, Leslie Grasse, Lakesla Iles, Geoffrey Bartholomeusz, Felipe Samaniego, Robert Z Orlowski, Joya Chandra.

   Aim: Multiple myeloma (MM) is a hematological malignancy of antibody-producing mature B cells or plasma cells. The proteasome inhibitor, bortezomib, was the first-in-class compound to be FDA approved for MM and is frequently utilized in induction therapy. However, bortezomib refractory disease is a major clinical concern, and the efficacy of the pan-histone deacetylase inhibitor (HDACi), panobinostat, in bortezomib refractory disease indicates that HDAC targeting is a viable strategy. Here, we utilized isogenic bortezomib resistant models to profile HDAC expression and define baseline and HDACi-induced expression patterns of individual HDAC family members in sensitive vs. resistant cells to better understanding the potential for targeting these enzymes.
Methods: Gene expression of HDAC family members in two sets of isogenic bortezomib sensitive or resistant myeloma cell lines was examined. These cell lines were subsequently treated with HDAC inhibitors: panobinostat or vorinostat, and HDAC expression was evaluated. CRISPR/Cas9 knockdown and pharmacological inhibition of specific HDAC family members were conducted.
Results: Interestingly, HDAC6 and HDAC7 were significantly upregulated and downregulated, respectively, in bortezomib-resistant cells. Panobinostat was effective at inducing cell death in these lines and modulated HDAC expression in cell lines and patient samples. Knockdown of HDAC7 inhibited cell growth while pharmacologically inhibiting HDAC6 augmented cell death by panobinostat.
Conclusion: Our data revealed heterogeneous expression of individual HDACs in bortezomib sensitive vs. resistant isogenic cell lines and patient samples treated with panobinostat. Cumulatively our findings highlight distinct roles for HDAC6 and HDAC7 in regulating cell death in the context of bortezomib resistance.

Keywords:  HDAC6; HDAC7; Histone deacetylase; bortezomib resistance; selective HDAC inhibitors

DOI:  https://doi.org/10.20517/cdr.2021.44
Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021 2100-2103

Computational Prediction of lncRNA-Protein Interactions using Machine learning.

Muhammad Mushtaq, Hammad Naveed, Zoya Khalid.

Long non-coding RNAs have generated much scientific interest because of their functional significance in regulating various biological processes and also their dysfunction has been implicated in disease progression. LncRNAs usually bind with proteins to perform their function. The experimental approaches for identifying these interactions are time taking and expensive. Lately, numerous method on predicting lncRNA-protein interactions have been reported yet, they all have some prevalent drawbacks that limit their prediction performance. In this research, we proposed a computational method based on a similarity scheme that integrates features derived from sequence and structure similarities. When compared with the state of the art, the proposed method has achieved highest performance with accuracy and F1 measure of 98.6% and 98.7% using XGBoost as classifier. Our results showed that by combining sequence and structure based features the lncRNA protein interactions can be better predicted and can also complement the experimental techniques for this task.Clinical Relevance- The lncRNA-protein interactions play significant role in regulating various biological processes. This can help in providing early diagnosis and better treatment for cancer related diseases.

DOI: https://doi.org/10.1109/EMBC46164.2021.9630282
ACS Sens. 2021 Dec 08.

Tracking the Dynamic Histone Methylation of H3K27 in Live Cancer Cells.

Ya Gong, Chujun Wei, Leonardo Cheng, Fengyi Ma, Shaoying Lu, Qin Peng, Longwei Liu, Yingxiao Wang.

  Histone methylations play a crucial role in chromatin remodeling and genome regulations. However, there is a lack of tools to visualize these histone modifications with high spatiotemporal resolutions in live cells. We have developed a biosensor based on fluorescence resonance energy transfer (FRET) and incorporated it into nucleosomes, capable of monitoring the trimethylation of H3K27 (H3K27me3) in live cells. We also revealed that the performance of the FRET biosensor can be significantly improved by adjusting the linkers within the biosensor. An improved biosensor enables the live-cell imaging of different histone methylation status, induced by the suppressive H3.3K27M or existing in breast cancer cells with varying genetic backgrounds. We have further applied the biosensor to reveal the dynamic coupling between H3K27me3 changes and caspase activity representing the initiation of apoptosis in cancer cells by imaging both H3K27me3 and caspase activity simultaneously in the same live cells. Thus, this new FRET biosensor can provide a powerful tool to visualize the epigenetic regulation in live cells with high spatial temporal resolutions.

Keywords:  FRET; H3K27me3; apoptosis; histone modification; live-cell imaging

DOI:  https://doi.org/10.1021/acssensors.1c01670
Front Pharmacol. 2021 ;12 771588

Acetylation in Tumor Immune Evasion Regulation.

Jun Lu, Xiang He, Lijuan Zhang, Ran Zhang, Wenzheng Li.

  Acetylation is considered as one of the most common types of epigenetic modifications, and aberrant histone acetylation modifications are associated with the pathological process of cancer through the regulation of oncogenes and tumor suppressors. Recent studies have shown that immune system function and tumor immunity can also be affected by acetylation modifications. A comprehensive understanding of the role of acetylation function in cancer is essential, which may help to develop new therapies to improve the prognosis of cancer patients. In this review, we mainly discussed the functions of acetylase and deacetylase in tumor, immune system and tumor immunity, and listed the information of drugs targeting these enzymes in tumor immunotherapy.

Keywords:  acetylases; acetylated modifications; cancer immunotherapy; deacetylases; tumor immunity

DOI:  https://doi.org/10.3389/fphar.2021.771588
Genomics. 2021 Dec 01. pii: S0888-7543(21)00416-X. [Epub ahead of print]

A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver.

Anjana Ramdas Nair, Priyanka Lakhiani, Chi Zhang, Filippo Macchi, Kirsten C Sadler.

  Restoring homeostasis following proteostatic stress hinges on a stress-specific transcriptional signature. How these signatures are regulated is unknown. We use functional genomics to uncover how activating transcription factor 6 (ATF6), a central factor in the unfolded protein response, regulates its target genes in response to toxicant induced and physiological stress in the liver. We identified 652 conserved putative ATF6 targets (CPATs), which functioned in metabolism, development and proteostasis. Strikingly, Atf6 activation in the zebrafish liver by transgenic nAtf6 overexpression, ethanol and arsenic exposure resulted in a distinct CPAT signature for each; with only 34 CPATs differentially expressed in all conditions. In contrast, during liver regeneration in mice resulted in a dynamic differential expression pattern of 53% of CPATs. These CPATs were distinguished by residing in open chromatin, H3K4me3 occupancy and the absence of H3K27me3 on their promoters. This suggests that a permissive epigenetic landscape allows stress-specific Atf6 target gene expression.

Keywords:  ATF6; Chromatin; Epigenome; Liver; Unfolded Protein response

DOI:  https://doi.org/10.1016/j.ygeno.2021.11.034
Front Oncol. 2021 ;11 742460

Autophagy-Induced HDAC6 Activity During Hypoxia Regulates Mitochondrial Energy Metabolism Through the β-Catenin/COUP-TFII Axis in Hepatocellular Carcinoma Cells.

Xiaoyu Yan, Xianzhi Qu, Buhan Liu, Yuanxin Zhao, Long Xu, Sihang Yu, Jian Wang, Liying Wang, Jing Su.

  Hypoxia is one of the main driving forces that results in poor outcomes and drug resistance in hepatocellular carcinoma (HCC). As the critical cellular oxygen sensor, mitochondria respond to hypoxic stress by sending retrograde signals to the nucleus that initiate adaptive metabolic responses and maintain the survival of HCC cells. Increasing evidence suggested autophagy contributes to sustain mitochondrial metabolic and quality control. Understanding how mitochondria communicate with the nucleus and alter transcription may provide promising targets for HCC treatment. In this study, we found mitochondrial undergoes selective degradation by autophagy under hypoxia. Furthermore, autophagy-activated HDAC6 not only promoted the nuclear translocation of β-catenin but also increased the affinity of β-catenin to the transcription repressor chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TF II), which suppressed mitochondrial oxidative phosphorylation-related genes transcription. Our data showed that autophagy served as a critical mediator of integrating mitochondrial energy metabolism and nuclear transcription. HDAC6 may be a potential target for reducing the survival of HCC cells by interrupting mitochondria-nucleus crosstalk.

Keywords:  HDAC6; autophagy; hepatocellular carcinoma; hypoxia; mitochondrial energy metabolism; β-catenin

DOI:  https://doi.org/10.3389/fonc.2021.742460
Front Pharmacol. 2021 ;12 770846

Peiminine Induces G0/G1-Phase Arrest, Apoptosis, and Autophagy via the ROS/JNK Signaling Pathway in Human Osteosarcoma Cells in Vitro and in Vivo.

Lei Yu, Yuxi Chen, Shaohui Yuan, Yang Cao, Zhenggang Bi.

  Aims: Peiminine has been reported to have various pharmacological properties, including anticancer activity. In this study, we investigated the effect of this alkaloid on osteosarcoma and explored the underlying mechanisms. Methods: To evaluate the antiosteosarcoma effects of peiminine in vitro, cell viability was assessed by CCK-8 and live/dead assays; the effects of the drug on apoptosis and the cell cycle were examined by flow cytometry; the effects on cell migration and invasion were detected by wound healing and Transwell assays, respectively, while its effects on autophagy were observed by transmission electron microscopy and an LC3 fluorescent puncta formation assay. The role of autophagy in the peiminine-mediated effects in osteosarcoma cells was evaluated by CCK-8 assay and western blotting after the application of the autophagy inhibitor chloroquine. The effect of peiminine on reactive oxygen species (ROS) production was analyzed using fluorescence confocal microscopy and spectrophotometry. Additionally, peiminine-treated osteosarcoma cells were exposed to SP600125, a JNK inhibitor, and N-acetylcysteine, a ROS scavenger, after which the contribution of the ROS/JNK signaling pathway to osteosarcoma was assessed using cell viability and LC3 fluorescent puncta formation assays, flow cytometry, and western blotting. A xenograft mouse model of osteosarcoma was generated to determine the antitumor effects of peiminine in vivo. Results: Peiminine suppressed proliferation and metastasis and induced cell cycle arrest, apoptosis, and autophagy in osteosarcoma cells. These anticancer effects of peiminine were found to be dependent on intracellular ROS generation and activation of the JNK pathway. In line with these results, peiminine significantly inhibited xenograft tumor growth in vivo. Conclusions: Peiminine induced G0/G1-phase arrest, apoptosis, and autophagy in human osteosarcoma cells via the ROS/JNK signaling pathway both in vitro and in vivo. Our study may provide an experimental basis for the evaluation of peiminine as an alternative drug for the treatment of osteosarcoma.

Keywords:  apoptosis; autophagy; c-Jun N-terminal kinase JNK; osteosarcoma; peiminine; reactive oxygen species ROS

DOI:  https://doi.org/10.3389/fphar.2021.770846
NPJ Syst Biol Appl. 2021 Dec 09. 7(1): 45

Constructing gene regulatory networks using epigenetic data.

Abhijeet Rajendra Sonawane, Dawn L DeMeo, John Quackenbush, Kimberly Glass.

The biological processes that drive cellular function can be represented by a complex network of interactions between regulators (transcription factors) and their targets (genes). A cell's epigenetic state plays an important role in mediating these interactions, primarily by influencing chromatin accessibility. However, how to effectively use epigenetic data when constructing a gene regulatory network remains an open question. Almost all existing network reconstruction approaches focus on estimating transcription factor to gene connections using transcriptomic data. In contrast, computational approaches for analyzing epigenetic data generally focus on improving transcription factor binding site predictions rather than deducing regulatory network relationships. We bridged this gap by developing SPIDER, a network reconstruction approach that incorporates epigenetic data into a message-passing framework to estimate gene regulatory networks. We validated SPIDER's predictions using ChIP-seq data from ENCODE and found that SPIDER networks are both highly accurate and include cell-line-specific regulatory interactions. Notably, SPIDER can recover ChIP-seq verified transcription factor binding events in the regulatory regions of genes that do not have a corresponding sequence motif. The networks estimated by SPIDER have the potential to identify novel hypotheses that will allow us to better characterize cell-type and phenotype specific regulatory mechanisms.

DOI: https://doi.org/10.1038/s41540-021-00208-3
Org Biomol Chem. 2021 Dec 08.

Amide-derived lysine analogues as substrates and inhibitors of histone lysine methyltransferases and acetyltransferases.

Jordi C J Hintzen, Jona Merx, Marijn N Maas, Sabine G H A Langens, Paul B White, Thomas J Boltje, Jasmin Mecinović.

Histone lysine methyltransferases and acetyltransferases are two classes of epigenetic enzymes that play pivotal roles in human gene regulation. Although they both recognise and posttranslationally modify lysine residues in histone proteins, their difference in histone peptide-based substrates and inhibitors remains to be firmly established. Here, we have synthesised lysine mimics that posses an amide bond linker in the side chain, incorporated them into histone H3 tail peptides, and examined synthetic histone peptides as substrates and inhibitors for human lysine methyltransferases and acetyltransferases. This work demonstrates that histone lysine methyltransferases G9a and GLP do catalyse methylation of the most similar lysine mimic, whereas they typically do not tolerate more sterically demanding side chains. In contrast, histone lysine acetyltransferases GCN5 and PCAF do not catalyse acetylation of the same panel of lysine analogues. Our results also identify potent H3-based inhibitors of GLP methyltransferase, providing a basis for development of peptidomimetics for targeting KMT enzymes.

DOI: https://doi.org/10.1039/d1ob02191e