bims-ectoca 2021-10-31 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2021–10–31
nine papers selected by
Ankita Daiya, Birla Institute of Technology and Science

The Emerging Roles of Long Noncoding RNAs as Hallmarks of Lung Cancer.
Chemical biology approaches to study histone interactors.
Assessing the in vitro Binding Specificity of Histone Modification Reader Proteins Using Histone Peptide Arrays.
Mitochondria govern histone acetylation in colorectal cancer.
G9a: An Emerging Epigenetic Target for Melanoma Therapy.
Histone Deacetylase Inhibitors: Providing New Insights and Therapeutic Avenues for Unlocking Human Birth.
H3K36 trimethylation-mediated biological functions in cancer.
Crosstalk between autophagy inhibitors and endosome-related secretory pathways: a challenge for autophagy-based treatment of solid cancers.
Cytoskeletal Actin Structure in Osteosarcoma Cells Determines Metastatic Phenotype via Regulating Cell Stiffness, Migration, and Transmigration.

Front Oncol. 2021 ;11 761582

The Emerging Roles of Long Noncoding RNAs as Hallmarks of Lung Cancer.

Jun Jiang, Yuan Lu, Fang Zhang, Jie Huang, Xin-Ling Ren, Rui Zhang.

  Noncoding ribonucleic acids (ncRNAs) are closely associated with tumor initiation, growth, and progress in lung cancer. Long ncRNAs (lncRNAs), as one of the three subclasses of ncRNAs, play important roles in chromatin modification, transcription, and post-transcriptional processing. Various lncRNAs have recently been reported to be dysfunctional or dysregulated in cancers and have pro- or anti-tumor potential. Importantly, as a new class of cancer biomarkers, studies have demonstrated the plausibility of using certain subsets of lncRNAs as promising diagnostic, therapeutic, or prognostic strategies to manage cancers. This review focuses on lncRNAs associated with hallmarks of lung cancer, especially those discovered in the last five years. The expression levels of these lncRNAs in tumor samples are discussed, alongside their mechanisms of action, drug resistance, and potential as diagnostic and prognostic markers for lung cancer.

Keywords:  cancer treatment; lncRNA; lung cancer; predictive biomarkers; prognostic biomarkers

DOI:  https://doi.org/10.3389/fonc.2021.761582
Biochem Soc Trans. 2021 Oct 28. pii: BST20210772. [Epub ahead of print]

Chemical biology approaches to study histone interactors.

Antony J Burton, Ghaith M Hamza, Andrew X Zhang, Tom W Muir.

  Protein-protein interactions (PPIs) in the nucleus play key roles in transcriptional regulation and ensure genomic stability. Critical to this are histone-mediated PPI networks, which are further fine-tuned through dynamic post-translational modification. Perturbation to these networks leads to genomic instability and disease, presenting epigenetic proteins as key therapeutic targets. This mini-review will describe progress in mapping the combinatorial histone PTM landscape, and recent chemical biology approaches to map histone interactors. Recent advances in mapping direct interactors of histone PTMs as well as local chromatin interactomes will be highlighted, with a focus on mass-spectrometry based workflows that continue to illuminate histone-mediated PPIs in unprecedented detail.

Keywords:  chemical biology; chromatin; epigenetics; mass spectrometry; post translational modification; protein–protein interactions

DOI:  https://doi.org/10.1042/BST20210772
Bio Protoc. 2021 Sep 20. 11(18): e4168

Assessing the in vitro Binding Specificity of Histone Modification Reader Proteins Using Histone Peptide Arrays.

Mark W Soo, Arneet L Saltzman.

  In the field of chromatin biology, a major goal of understanding the roles of histone post-translational modifications is to identify the proteins and domains that recognize these modifications. Synthetic histone peptides containing one or more modifications are a key tool to probe these interactions in pull-down assays with recombinant proteins or cell lysates. Building on these approaches, the binding specificity of a protein of interest can be screened against many histone peptides in parallel using a peptide array. In this protocol, we describe the expression and purification of a recombinant protein of interest in bacteria, followed by an assay for binding to histone post-translational modifications using a commercially available histone peptide array. The purification uses a versatile dual-tagging and cleavage strategy and equipment commonly available in a molecular biology laboratory. Graphic abstract: Overview of protocol for purifying recombinant protein and hybridizing to a histone peptide array.

Keywords:  Affinity purification; Chromatin; Chromodomain; Epigenetics; Histone modifications; Histone peptide array; Histone tail; Recombinant protein

DOI:  https://doi.org/10.21769/BioProtoc.4168
J Pathol. 2021 Oct 26.

Mitochondria govern histone acetylation in colorectal cancer.

Kenji Ohshima, Ryo Oi, Satoshi Nojima, Eiichi Morii.

  Cancer cells have an altered metabolic state that supports their growth; for example, aerobic glycolysis, known as the Warburg effect. Colorectal cancer cells have been reported to exhibit the Warburg effect and mainly rely on glycolysis for progression and have dysfunctional mitochondria. So far, how mitochondrial function influences the properties of colorectal cancer cells is unclear. Here, we demonstrated that mitochondria maintain histone acetylation, in particular H3K27ac, a surrogate epigenomic marker of active super-enhancers, in colorectal cancer cells. Immunohistochemistry was used on human colorectal adenocarcinoma specimens and showed that mitochondrial mass and H3K27ac marks were increased in adenocarcinoma lesions compared to adjacent non-neoplastic mucosa. Immunoblotting after using inhibitors of the mitochondrial respiratory complex or mitochondrial DNA-depleted human colorectal cancer cells revealed that mitochondria maintained pan-histone acetylation and H3K27ac marks. Notably, anchorage-independent growth, a feature of cancer, increased mitochondrial mass and H3K27ac marks in human colorectal cancer cells. These findings indicate that mitochondria in human colorectal cancer cells are not dysfunctional, as formerly believed, but function as inducers of histone acetylation. This article is protected by copyright. All rights reserved.

Keywords:  Anchorage-independent growth; Colorectal cancer; H3K27ac; Histone acetylation; Mitochondria

DOI:  https://doi.org/10.1002/path.5818
Epigenomes. 2021 Dec;pii: 23. [Epub ahead of print]5(4):

G9a: An Emerging Epigenetic Target for Melanoma Therapy.

Jessica L Flesher, David E Fisher.

  Epigenetic regulation is a crucial component of DNA maintenance and cellular identity. As our understanding of the vast array of proteins that contribute to chromatin accessibility has advanced, the role of epigenetic remodelers in disease has become more apparent. G9a is a histone methyltransferase that contributes to immune cell differentiation and function, neuronal development, and has been implicated in diseases, including cancer. In melanoma, recurrent mutations and amplifications of G9a have led to its identification as a therapeutic target. The pathways that are regulated by G9a provide an insight into relevant biomarkers for patient stratification. Future work is aided by the breadth of literature on G9a function during normal differentiation and development, along with similarities to EZH2, another histone methyltransferase that forms a synthetic lethal relationship with members of the SWI/SNF complex in certain cancers. Here, we review the literature on G9a, its role in melanoma, and lessons from EZH2 inhibitor studies.

Keywords:  EZH2; G9a; epigenetic inhibitors; melanoma

DOI:  https://doi.org/10.3390/epigenomes5040023
Reprod Sci. 2021 Oct 28.

Histone Deacetylase Inhibitors: Providing New Insights and Therapeutic Avenues for Unlocking Human Birth.

Marina Ilicic, Tamas Zakar, Amy Gregson, Waleed M Hussein, Roger Smith, Jonathan W Paul.

  The pregnant uterus remains relaxed throughout fetal gestation before transforming to a contractile phenotype at term to facilitate birth. Despite ongoing progress, the precise mechanisms that regulate this phenotypic transformation are not yet understood. This knowledge gap limits our understanding of how dysregulation of uterine smooth muscle biology contributes to life-threatening obstetric complications, including preterm birth, and hampers our ability to develop effective therapeutic intervention strategies. Protein acetylation plays a vital role in regulating protein structure, function, and subcellular localization, as well as gene transcription availability through regulating chromatin condensation. Histone deacetylase inhibitors (HDACis) are a class of compounds that block the removal of acetyl functional groups from proteins and, as such, have profound effects on important cellular events, including phenotypic transformation. A large body of data now demonstrates that HDACis have profound effects on pregnant human myometrium. Studies to date show that HDACis operate through both genomic and non-genomic mechanisms to affect myometrial function and phenotype. Interestingly, the effects of HDACis on pregnant myometrium are largely "pro-relaxation," including the direct inhibition of contractile machinery as well as repression of pro-labor genes. The "dual action" effects of HDACis make them a powerful tool for unlocking the regulatory processes that underpin myometrial phenotypic transformation and raises prospects of their therapeutic applications. Here, we review the new insights into human myometrial biology that have garnered through the application of HDACis and explore their potential therapeutic application toward the development of novel preterm birth prevention strategies.

Keywords:  Epigenetics; Histone deacetylase; Histone deacetylase inhibitors; Parturition; Progesterone; Trichostatin A

DOI:  https://doi.org/10.1007/s43032-021-00778-x
Clin Epigenetics. 2021 Oct 29. 13(1): 199

H3K36 trimethylation-mediated biological functions in cancer.

Chu Xiao, Tao Fan, He Tian, Yujia Zheng, Zheng Zhou, Shuofeng Li, Chunxiang Li, Jie He.

  Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in multiple cellular processes. As a conserved histone methylation mark, histone 3 lysine 36 trimethylation (H3K36me3) can mediate multiple transcriptional-related events, such as the regulation of transcriptional activity, transcription elongation, pre-mRNA alternative splicing, and RNA m6A methylation. Additionally, H3K36me3 also contributes to DNA damage repair. Given the crucial function of H3K36me3 in genome regulation, the roles of H3K36me3 and its sole methyltransferase SETD2 in pathogenesis, especially malignancies, have been emphasized in many studies, and it is conceivable that disruption of histone methylation regulatory network composed of "writer", "eraser", "reader", and the mutation of H3K36me3 codes have the capacity of powerfully modulating cancer initiation and development. Here we review H3K36me3-mediated biological processes and summarize the latest findings regarding its role in cancers. We highlight the significance of epigenetic combination therapies in cancers.

Keywords:  Epigenetic therapy; H3K36me3; Histone modification; Solid tumor

DOI:  https://doi.org/10.1186/s13148-021-01187-2
Mol Cancer. 2021 Oct 27. 20(1): 140

Crosstalk between autophagy inhibitors and endosome-related secretory pathways: a challenge for autophagy-based treatment of solid cancers.

Martina Raudenska, Jan Balvan, Michal Masarik.

  Autophagy is best known for its role in organelle and protein turnover, cell quality control, and metabolism. The autophagic machinery has, however, also adapted to enable protein trafficking and unconventional secretory pathways so that organelles (such as autophagosomes and multivesicular bodies) delivering cargo to lysosomes for degradation can change their mission from fusion with lysosomes to fusion with the plasma membrane, followed by secretion of the cargo from the cell. Some factors with key signalling functions do not enter the conventional secretory pathway but can be secreted in an autophagy-mediated manner.Positive clinical results of some autophagy inhibitors are encouraging. Nevertheless, it is becoming clear that autophagy inhibition, even within the same cancer type, can affect cancer progression differently. Even next-generation inhibitors of autophagy can have significant non-specific effects, such as impacts on endosome-related secretory pathways and secretion of extracellular vesicles (EVs). Many studies suggest that cancer cells release higher amounts of EVs compared to non-malignant cells, which makes the effect of autophagy inhibitors on EVs secretion highly important and attractive for anticancer therapy. In this review article, we discuss how different inhibitors of autophagy may influence the secretion of EVs and summarize the non-specific effects of autophagy inhibitors with a focus on endosome-related secretory pathways. Modulation of autophagy significantly impacts not only the quantity of EVs but also their content, which can have a deep impact on the resulting pro-tumourigenic or anticancer effect of autophagy inhibitors used in the antineoplastic treatment of solid cancers.

Keywords:  Amphisomes; Autophagy; Autophagy inhibitors; Cancer; Endosomes; Exosomes; Extracellular vesicles; Multivesicular bodies; Non-conventional secretory pathways

DOI:  https://doi.org/10.1186/s12943-021-01423-6
Curr Issues Mol Biol. 2021 Sep 24. 43(3): 1255-1266

Cytoskeletal Actin Structure in Osteosarcoma Cells Determines Metastatic Phenotype via Regulating Cell Stiffness, Migration, and Transmigration.

Kouji Kita, Kunihiro Asanuma, Takayuki Okamoto, Eiji Kawamoto, Koichi Nakamura, Tomohito Hagi, Tomoki Nakamura, Motomu Shimaoka, Akihiro Sudo.

  Osteosarcoma is the most common primary malignant bone tumor. The cause of death due to osteosarcoma is typically a consequence of metastasis to the lung. Controlling metastasis leads to improved prognosis for osteosarcoma patients. The cell stiffness of several tumor types is involved in metastatic potential; however, it is unclear whether the metastatic potential of osteosarcoma depends on cell stiffness. In this study, we analyzed the cell stiffness of the low metastatic Dunn cell line and its highly metastatic LM8 subline, and compared actin organization, cell proliferation, and metastasis. Actin cytoskeleton, polymerization, stiffness, and other cellular properties were analyzed. The organization of the actin cytoskeleton was evaluated by staining F-actin with Alexa Fluor 488 phalloidin. Cell stiffness was measured using Atomic Force Microscopy (AFM). Cell proliferation, migration, invasion, and adhesion were also evaluated. All experiments were performed using mouse osteosarcoma cell lines cultured in the absence and presence of cytochalasin. In LM8 cells, actin polymerization was strongly suppressed and actin levels were significantly lower than in Dunn cells. Stiffness evaluation revealed that LM8 cells were significantly softer than Dunn. Young's modulus images showed more rigid fibrillar structures were present in Dunn cells than in LM8 cells. LM8 cells also exhibited a significantly higher proliferation. The migration and invasion potential were also higher in LM8 cells, whereas the adhesion potential was higher in Dunn cells. The administration of cytochalasin resulted in actin filament fragmentation and decreased actin staining intensity and cell stiffness in both LM8 and Dunn cells. Cells with high metastatic potential exhibited lower actin levels and cell stiffness than cells with low metastatic potential. The metastatic phenotype is highly correlated to actin status and cell stiffness in osteosarcoma cells. These results suggest that evaluation of actin dynamics and cell stiffness is an important quantitative diagnostic parameter for predicting metastatic potential. We believe that these parameters represent new reliable quantitative indicators that can facilitate the development of new drugs against metastasis.

Keywords:  actin cytoskeleton; atomic force microscopy; cell stiffness; metastasis; osteosarcoma cell line

DOI:  https://doi.org/10.3390/cimb43030089