bims-ectoca 2024-06-23 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024‒06‒23
twelve papers selected by
Ankita Daiya, Birla Institute of Technology and Science

The condensation of HP1α/Swi6 imparts nuclear stiffness.
p53 ensures the normal behavior and modification of G1/S-specific histone H3.1 in the nucleus.
Melittin inactivates YAP/HIF-1α pathway via up-regulation of LATS2 to inhibit hypoxia-induced proliferation, glycolysis and angiogenesis in NSCLC.
Comprehensive multimodal and multiomic profiling reveals epigenetic and transcriptional reprogramming in lung tumors.
EZH2-associated tumor malignancy: A prominent target for cancer treatment.
Nuclear periphery and its mechanical regulation in cell fate transitions.
The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes.
Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches.
Cellular and epigenetic perspective of protein stability and its implications in the biological system.
Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA damage response inhibitors.
Beyond histones: the elusive substrates of chromatin regulators.
Differential effects of montelukast and zafirlukast on MDA‑MB‑231 triple‑negative breast cancer cells: Cell cycle regulation, apoptosis, autophagy, DNA damage and endoplasmic reticulum stress.

Cell Rep. 2024 Jun 19. pii: S2211-1247(24)00701-0. [Epub ahead of print]43(7): 114373

The condensation of HP1α/Swi6 imparts nuclear stiffness.

Jessica F Williams, Ivan V Surovtsev, Sarah M Schreiner, Ziyuan Chen, Gulzhan Raiymbek, Hang Nguyen, Yan Hu, Julie S Biteen, Simon G J Mochrie, Kaushik Ragunathan, Megan C King.

  Biomolecular condensates have emerged as major drivers of cellular organization. It remains largely unexplored, however, whether these condensates can impart mechanical function(s) to the cell. The heterochromatin protein HP1α (Swi6 in Schizosaccharomyces pombe) crosslinks histone H3K9 methylated nucleosomes and has been proposed to undergo condensation to drive the liquid-like clustering of heterochromatin domains. Here, we leverage the genetically tractable S. pombe model and a separation-of-function allele to elucidate a mechanical function imparted by Swi6 condensation. Using single-molecule imaging, force spectroscopy, and high-resolution live-cell imaging, we show that Swi6 is critical for nuclear resistance to external force. Strikingly, it is the condensed yet dynamic pool of Swi6, rather than the chromatin-bound molecules, that is essential to imparting mechanical stiffness. Our findings suggest that Swi6 condensates embedded in the chromatin meshwork establish the emergent mechanical behavior of the nucleus as a whole, revealing that biomolecular condensation can influence organelle and cell mechanics.

Keywords:  CP: Cell biology; CP: Molecular biology; HP1; S. pombe; Swi6; biomolecular condensation; biophysics; heterochromatin; microscopy; nuclear mechanics

DOI:  https://doi.org/10.1016/j.celrep.2024.114373
Life Sci Alliance. 2024 Sep;pii: e202402835. [Epub ahead of print]7(9):

p53 ensures the normal behavior and modification of G1/S-specific histone H3.1 in the nucleus.

Tsukasa Oikawa, Junya Hasegawa, Haruka Handa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe.

H3.1 histone is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, as a new component of duplicating nucleosomes. Here, we found that p53 is necessary to secure the normal behavior and modification of H3.1 in the nucleus during the G1/S phase, in which p53 increases C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) levels and decreases enhancer of zeste homolog 2 (EZH2) levels in the H3.1 interactome. In the absence of p53, H3.1 molecules tended to be tethered at or near the nuclear envelope (NE), where they were predominantly trimethylated at lysine 27 (H3K27me3) by EZH2, without forming nucleosomes. This accumulation was likely caused by the high affinity of H3.1 toward phosphatidic acid (PA). p53 reduced nuclear PA levels by increasing levels of CTDNEP1, which activates lipin to convert PA into diacylglycerol. We moreover found that the cytosolic H3 chaperone HSC70 attenuates the H3.1-PA interaction, and our molecular imaging analyses suggested that H3.1 may be anchored around the NE after their nuclear entry. Our results expand our knowledge of p53 function in regulation of the nuclear behavior of H3.1 during the G1/S phase, in which p53 may primarily target nuclear PA and EZH2.

DOI: https://doi.org/10.26508/lsa.202402835
Clinics (Sao Paulo). 2024 ;pii: S1807-5932(24)00084-X. [Epub ahead of print]79 100407

Melittin inactivates YAP/HIF-1α pathway via up-regulation of LATS2 to inhibit hypoxia-induced proliferation, glycolysis and angiogenesis in NSCLC.

Hao Li.

  BACKGROUND: NSCLC is one of the most common causes of death. The hypoxia microenvironment contributes to cancer progression. The purpose was to explore the effects and mechanism of melittin on NSCLC cells in the hypoxic microenvironment.METHODS: NSCLC cell lines (A549 and H1299) were cultured in normoxia or hypoxia conditions with or without melittin treatment. The viability of the cells was detected via MTT assay and the proliferation ability was evaluated by EdU assay. QRT-PCR was performed to evaluate GLUT1, LDHA, HK2, VEGF and LATS2 mRNA levels. Glucose transport was assessed by the 2-NBDG uptake assay. The angiogenesis was determined by the tubule formation assay. The protein expressions of GLUT1, LDHA, HK2, VEGF, LATS2, YAP, p-YAP and HIF-1α were detected via western blotting assay. The tumor formation assay was conducted to examine the roles of melittin and LATS2 in vivo.
RESULTS: Melittin inhibited hypoxia-induced cell viability, proliferation, glycolysis and angiogenesis as well as suppressed YAP binding to HIF-1α in NSCLC. Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2, ultimately inhibiting cancer progression of NSCLC. Moreover, melittin suppressed tumor growth via up-regulation of LATS2 in vivo.
CONCLUSION: Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2 to contribute to the development of NSCLC. Therefore, melittin is expected to become a potential prognostic drug for the therapy of NSCLC.

Keywords:  Angiogenesis; Glycolysis; LATS2; Melittin; Non-small cell lung cancer; Proliferation

DOI:  https://doi.org/10.1016/j.clinsp.2024.100407
bioRxiv. 2024 Jun 08. pii: 2024.06.06.597667. [Epub ahead of print]

Comprehensive multimodal and multiomic profiling reveals epigenetic and transcriptional reprogramming in lung tumors.

Peiyao Wu, Zhengzhi Liu, Lina Zheng, Zirui Zhou, Wei Wang, Chang Lu.

Epigenomic mechanisms are critically involved in mediation of genetic and environmental factors that underlie cancer development. Histone modifications represent highly informative epigenomic marks that reveal activation and repression of gene activities and dysregulation of transcriptional control due to tumorigenesis. Here, we present a comprehensive epigenomic and transcriptomic mapping of 18 tumor and 20 non-neoplastic tissues from non-small cell lung adenocarcinoma patients. Our profiling covers 5 histone marks including activating (H3K4me3, H3K4me1, and H3K27ac) and repressive (H3K27me3 and H3K9me3) marks and the transcriptome using only 20 mg of tissue per sample, enabled by low-input omic technologies. Using advanced integrative bioinformatic analysis, we uncovered cancer-driving signaling cascade networks, changes in 3D genome modularity, and differential expression and functionalities of transcription factors and noncoding RNAs. Many of these identified genes and regulatory molecules showed no significant change in their expression or a single epigenomic modality, emphasizing the power of integrative multimodal and multiomic analysis using patient samples.

DOI: https://doi.org/10.1101/2024.06.06.597667
Clin Genet. 2024 Jun 17.

EZH2-associated tumor malignancy: A prominent target for cancer treatment.

Maryam Sabour-Takanlou, Leila Sabour-Takanlou, Cigir Biray-Avci.

  The discussion in this review centers around the significant relationships between EZH2 and the initiation, progression, metastasis, metabolism, drug resistance, and immune regulation of cancer. Polycomb group (PcG) proteins, which encompass two primary Polycomb repressor complexes (PRC1 and PRC2), have been categorized. PRC2 consists mainly of four subunits, namely EZH2, EED, SUZ12, and RbAp46/48. As the crucial catalytic component within the PRC2 complex, EZH2 plays a pivotal role in controlling a wide range of biological processes. Overexpression/mutations of EZH2 have been detected in a wide variety of tumors. Several mechanisms of EZH regulation have been identified, including regulation EZH2 mRNA by miRNAs, LncRNAs, accessibility to DNA via DNA-binding proteins, post-translational modifications, and transcriptional regulation. EZH2 signaling triggers cancer progression and may intervene with anti-tumor immunity; therefore it has charmed attention as an effective therapeutic target in cancer therapy. Numerouss nucleic acid-based therapies have been used in the modification of EZH2. In addition to gene therapy approaches, pharmaceutical compounds can be used to target the EZH2 signaling pathway in the treatment of cancer. EZH2-associated tumor cells and immune cells enhance the effects of the immune response in a variety of human malignancies. The combination of epigenetic modifying agents, such as anti-EZH2 compounds with immunotherapy, could potentially be efficacious even in the context of immunosuppressive tumors. Summary, understanding the mechanisms underlying resistance to EZH2 inhibitors may facilitate the development of novel drugs to prevent or treat relapse in treated patients.

Keywords:  EZH2; PRC1; PRC2; cancer; epigenetic; treatment

DOI:  https://doi.org/10.1111/cge.14576
Curr Opin Struct Biol. 2024 Jun 17. pii: S0959-440X(24)00094-0. [Epub ahead of print]87 102867

Nuclear periphery and its mechanical regulation in cell fate transitions.

Rebecca K Stephens, Yekaterina A Miroshnikova.

Cell fate changes require rewiring of transcriptional programs to generate functionally specialized cell states. Reconfiguration of transcriptional networks requires overcoming epigenetic barriers imposed by silenced heterochromatin in order to activate lineage-specific genes. Further, cell fate decisions are made in a tissue-specific context, where cells are physically linked to each other as well as to the connective tissue environment. Here, cells are continuously exposed to a multitude of mechanical forces emanating from cellular dynamics in their local microenvironments, for example through cell movements, cell divisions, tissue contractions, or fluid flow. Through their ability to deform cellular structures and activate receptors, mechanical forces can be sensed at the plasma membrane, but also at the nuclear periphery through direct or cytoskeleton-mediated deformation of the nuclear envelope. This deformation and the associated signaling is capable of triggering changes in the mechanical state of the nuclear membranes, the organization and rigidity of the underlying nuclear lamina, compaction state of chromatin, and ultimately transcription. This review focuses on the role of nuclear architecture, particularly the nuclear lamina-chromatin interface, and its mechanical regulation in cell fate decisions as well as its physiological role in development and cellular reprogramming.

DOI: https://doi.org/10.1016/j.sbi.2024.102867
Cancers (Basel). 2024 Jun 01. pii: 2123. [Epub ahead of print]16(11):

The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes.

Francisco Gimeno-Valiente, Gerardo López-Rodas, Josefa Castillo, Luis Franco.

  Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing-which produces various mature mRNAs and, eventually, protein variants from a single gene-may also result in driving neoplastic transformation because of the different and often opposed functions of the variants of driver genes. The present review analyses the different alternative splicing events that result in driving neoplastic transformation, with an emphasis on their molecular mechanisms. To do this, we collected a list of 568 gene drivers of cancer and revised the literature to select those involved in the alternative splicing of other genes as well as those in which its pre-mRNA is subject to alternative splicing, with the result, in both cases, of producing an oncogenic isoform. Thirty-one genes fall into the first category, which includes splicing factors and components of the spliceosome and splicing regulators. In the second category, namely that comprising driver genes in which alternative splicing produces the oncogenic isoform, 168 genes were found. Then, we grouped them according to the molecular mechanisms responsible for alternative splicing yielding oncogenic isoforms, namely, mutations in cis splicing-determining elements, other causes involving non-mutated cis elements, changes in splicing factors, and epigenetic and chromatin-related changes. The data given in the present review substantiate the idea that aberrant splicing may regulate the activation of proto-oncogenes or inactivation of tumour suppressor genes and details on the mechanisms involved are given for more than 40 driver genes.

Keywords:  alternative splicing; cancer driver genes; chromatin; epigenetics; oncogenes; oncogenic isoforms; protein variants; splicing factors; splicing molecular mechanisms; tumour suppressor genes

DOI:  https://doi.org/10.3390/cancers16112123
Int J Mol Sci. 2024 May 29. pii: 5915. [Epub ahead of print]25(11):

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches.

Caterina Mancarella, Andrea Morrione, Katia Scotlandi.

  Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.

Keywords:  IGF system; PROTACs; RAGE; cancer; extracellular signals; extracellular vesicles; target therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25115915
Epigenomics. 2024 Jun 17. 1-22

Cellular and epigenetic perspective of protein stability and its implications in the biological system.

Nisha Manav, Bimal Prasad Jit, Babita Kataria, Ashok Sharma.

  Protein stability is a fundamental prerequisite in both experimental and therapeutic applications. Current advancements in high throughput experimental techniques and functional ontology approaches have elucidated that impairment in the structure and stability of proteins is intricately associated with the cause and cure of several diseases. Therefore, it is paramount to deeply understand the physical and molecular confounding factors governing the stability of proteins. In this review article, we comprehensively investigated the evolution of protein stability, examining its emergence over time, its relationship with organizational aspects and the experimental methods used to understand it. Furthermore, we have also emphasized the role of Epigenetics and its interplay with post-translational modifications (PTMs) in regulating the stability of proteins.

Keywords:  LncRNAs; epigenetic players; epigenetics; histone modifications; molecular crowding; non-enzymatic PTMs; post-translational modifications; protein evolution; protein stability

DOI:  https://doi.org/10.1080/17501911.2024.2351788
NPJ Syst Biol Appl. 2024 Jun 21. 10(1): 68

Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA damage response inhibitors.

Orsolya Papp, Viktória Jordán, Szabolcs Hetey, Róbert Balázs, Valér Kaszás, Árpád Bartha, Nóra N Ordasi, Sebestyén Kamp, Bálint Farkas, Jay Mettetal, Jonathan R Dry, Duncan Young, Ben Sidders, Krishna C Bulusu, Daniel V Veres.

Combination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell™. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC = 0.62, AUC = 0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell 'avatars' capture the biological complexity of their in vitro counterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability.

DOI: https://doi.org/10.1038/s41540-024-00394-w
Genes Dev. 2024 Jun 12.

Beyond histones: the elusive substrates of chromatin regulators.

Mattias Mannervik.

  Gene transcription is intimately linked to chromatin state and histone modifications. However, the enzymes mediating these post-translational modifications have many additional, nonhistone substrates, making it difficult to ascribe the most relevant modification. In this issue of Genes & Development, Crain and colleagues (doi:10.1101/gad.351698.124) have combined a powerful histone replacement system with mutational analysis of a chromatin regulator and a chromatin reader in Drosophila melanogaster Importantly, they discovered that genes controlled by the histone 4 lysine 20 (H4K20) methyltransferase Set8 and the protein recognizing H4K20 monomethylation, L(3)mbt, differ substantially from those affected by mutation of H4K20 itself. This demonstrates that H4K20 is not the key substrate for Set8 but that methylation of other, unidentified proteins mediates its effects on transcription.

Keywords:  Drosophila melanogaster; H4K20me1; L(3)mbt; Set8; chromatin; epigenetics; gene expression; genomics

DOI:  https://doi.org/10.1101/gad.351969.124
Mol Med Rep. 2024 Aug;pii: 141. [Epub ahead of print]30(2):

Differential effects of montelukast and zafirlukast on MDA‑MB‑231 triple‑negative breast cancer cells: Cell cycle regulation, apoptosis, autophagy, DNA damage and endoplasmic reticulum stress.

Pornpun Vivithanaporn, Thanaporn Sriwantana, Kanokpan Krueaprasertkul, Nathawut Sibmooh, Suttinee Phuagkhaopong, Piyanuch Wonganan.

  Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triple‑negative breast cancer MDA‑MB‑231 cells. By contrast, only zafirlukast induces G0/G1 cell cycle arrest. The present study compared the effects of these drugs on proteins regulating cell proliferation, apoptosis, autophagy, and endoplasmic reticulum (ER) and oxidative stress using reverse transcription‑quantitative PCR, western blotting and flow cytometry. The expression of proliferating markers, Ki‑67 and proliferating cell nuclear antigen, was decreased by both drugs. Zafirlukast, but not montelukast, decreased the expression of cyclin D1 and CDK4, disrupting progression from G1 to S phase. Zafirlukast also increased the expression of p27, a cell cycle inhibitor. Both drugs decreased the expression of anti‑apoptotic protein Bcl‑2 and ERK1/2 phosphorylation, and increased levels of the autophagy marker LC3‑II and DNA damage markers, including cleaved PARP‑1, phosphorylated (p)‑ATM and p‑histone H2AX. The number of caspase 3/7‑positive cells was greater in montelukast‑treated cells compared with zafirlukast‑treated cells. Montelukast induced higher levels of the ER stress marker CHOP compared with zafirlukast. Montelukast activated PERK, activating transcription factor 6 (ATF6) and inositol‑requiring enzyme type 1 (IRE1) pathways, while zafirlukast only stimulated ATF6 and IRE1 pathways. GSK2606414, a PERK inhibitor, decreased apoptosis mediated by montelukast, but did not affect zafirlukast‑induced cell death. The knockdown of CHOP by small interfering RNA reduced apoptosis triggered by montelukast and zafirlukast. In conclusion, the effects on cell cycle regulator proteins may contribute to cell cycle arrest caused by zafirlukast. The greater apoptotic effects of montelukast may be caused by the higher levels of activated caspase enzymes and the activation of three pathways of ER stress: PERK, ATF6, and IRE1.

Keywords:  CHOP; LC3; PARP‑1; caspase; cyclin D; endoplasmic reticulum stress

DOI:  https://doi.org/10.3892/mmr.2024.13265