bims-ectoca 2023-04-23 papers

Issue of 2023‒04‒23
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Sci Adv. 2023 Apr 21. 9(16): eadg6593

Epigenetic moonlighting: Catalytic-independent functions of histone modifiers in regulating transcription.

The past three decades have yielded a wealth of information regarding the chromatin regulatory mechanisms that control transcription. The "histone code" hypothesis-which posits that distinct combinations of posttranslational histone modifications are "read" by downstream effector proteins to regulate gene expression-has guided chromatin research to uncover fundamental mechanisms relevant to many aspects of biology. However, recent molecular and genetic studies revealed that the function of many histone-modifying enzymes extends independently and beyond their catalytic activities. In this review, we highlight original and recent advances in the understanding of noncatalytic functions of histone modifiers. Many of the histone modifications deposited by these enzymes-previously considered to be required for transcriptional activation-have been demonstrated to be dispensable for gene expression in living organisms. This perspective aims to prompt further examination of these enigmatic chromatin modifications by inspiring studies to define the noncatalytic "epigenetic moonlighting" functions of chromatin-modifying enzymes.

DOI: https://doi.org/10.1126/sciadv.adg6593

Methods Mol Biol. 2023 ;2634 285-314

Live-Cell Sender-Receiver Co-cultures for Quantitative Measurement of Paracrine Signaling Dynamics, Gene Expression, and Drug Response.

Michael Pargett, Abhineet R Ram, Vaibhav Murthy, Alexander E Davies.

Paracrine signaling is a fundamental process regulating tissue development, repair, and pathogenesis of diseases such as cancer. Herein we describe a method for quantitatively measuring paracrine signaling dynamics, and resultant gene expression changes, in living cells using genetically encoded signaling reporters and fluorescently tagged gene loci. We discuss considerations for selecting paracrine "sender-receiver" cell pairs, appropriate reporters, the use of this system to ask diverse experimental questions and screen drugs blocking intracellular communication, data collection, and the use of computational approaches to model and interpret these experiments.

Keywords: Cancer; Drug screening; ERK; Intercellular communication; Live-cell microscopy; MAPK; Single cell

DOI: https://doi.org/10.1007/978-1-0716-3008-2_13

Nucleus. 2023 Dec;14(1): 2202548

Lamin B1 overexpression alters chromatin organization and gene expression.

Jeanae M Kaneshiro, Juliana S Capitanio, Martin W Hetzer.

Peripheral heterochromatin positioning depends on nuclear envelope associated proteins and repressive histone modifications. Here we show that overexpression (OE) of Lamin B1 (LmnB1) leads to the redistribution of peripheral heterochromatin into heterochromatic foci within the nucleoplasm. These changes represent a perturbation of heterochromatin binding at the nuclear periphery (NP) through a mechanism independent from altering other heterochromatin anchors or histone post-translational modifications. We further show that LmnB1 OE alters gene expression. These changes do not correlate with different levels of H3K9me3, but a significant number of the misregulated genes were likely mislocalized away from the NP upon LmnB1 OE. We also observed an enrichment of developmental processes amongst the upregulated genes. ~74% of these genes were normally repressed in our cell type, suggesting that LmnB1 OE promotes gene de-repression. This demonstrates a broader consequence of LmnB1 OE on cell fate, and highlights the importance of maintaining proper levels of LmnB1.

Keywords: Chromatin organization; gene expression; heterochromatin; nuclear envelope; nuclear lamina

DOI: https://doi.org/10.1080/19491034.2023.2202548

Nat Commun. 2023 04 17. 14(1): 2140

Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer.

Nikhil B Ghate, Sungmin Kim, Yonghwan Shin, Jinman Kim, Michael Doche, Scott Valena, Alan Situ, Sangnam Kim, Suhn K Rhie, Heinz-Josef Lenz, Tobias S Ulmer, Shannon M Mumenthaler, Woojin An.

Our recent work has shown that DCAF1 (also known as VprBP) is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether DCAF1 also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that DCAF1 phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, DCAF1-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a mechanism underlying DCAF1-driven colonic tumorigenesis by linking DCAF1-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.

DOI: https://doi.org/10.1038/s41467-023-37883-1

Curr Pharm Des. 2023 Apr 13.

Advancing Tissue Factor-targeted Therapy for Osteosarcoma via Understanding its Role in the Tumor Microenvironment.

Jiro Ichikawa, Jonathan G Schoenecker, Rikito Tatsuno, Tomonori Kawasaki, Katsue Suzuki-Inoue, Hirotaka Haro.

Coagulation activation is associated with cancer progression and morbidity. Recently, mechanisms through which coagulation proteases drive the tumor microenvironment (TME) have been elucidated. This study aims to develop a new strategy dependent on the coagulation system for treating osteosarcoma (OS). We focused on tissue factor (TF), the main initiator of the extrinsic coagulant pathway, as a target for OS treatment. It was found that cell surface-TF, TF-positive extracellular vesicles, and TF-positive circulating tumor cells could drive progression, metastasis, and TME in carcinomas, including OS. Thus, targeting tumor-associated coagulation by focusing on TF, the principle catalyst of the extrinsic pathway, TF is a promising strategy treatment for OS.

Keywords: Osteosarcoma; Tissue factor; Tumor Microenvironment; Chemotherapy; Antibody-Drug-Conjugate; Heparin; Low molecular weight heparin

DOI: https://doi.org/10.2174/1381612829666230413094242

Cancer Drug Resist. 2023 ;6(1): 182-204

Heterotypic signaling of cancer-associated fibroblasts in shaping the cancer cell drug resistance.

Ramesh Butti, Ashwini Khaladkar, Priya Bhardwaj, Gopinath Prakasam.

The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.

Keywords: CAFs; ECM; Tumor microenvironment; drug resistance; heterogeneity; heterotypic signaling; metabolic reprogramming; natural products

DOI: https://doi.org/10.20517/cdr.2022.72

Cancer Res Commun. 2023 Apr;3(4): 564-575

Structurally Complex Osteosarcoma Genomes Exhibit Limited Heterogeneity within Individual Tumors and across Evolutionary Time.

Sanjana Rajan, Simone Zaccaria, Matthew V Cannon, Maren Cam, Amy C Gross, Benjamin J Raphael, Ryan D Roberts.

Osteosarcoma is an aggressive malignancy characterized by high genomic complexity. Identification of few recurrent mutations in protein coding genes suggests that somatic copy-number aberrations (SCNA) are the genetic drivers of disease. Models around genomic instability conflict-it is unclear whether osteosarcomas result from pervasive ongoing clonal evolution with continuous optimization of the fitness landscape or an early catastrophic event followed by stable maintenance of an abnormal genome. We address this question by investigating SCNAs in >12,000 tumor cells obtained from human osteosarcomas using single-cell DNA sequencing, with a degree of precision and accuracy not possible when inferring single-cell states using bulk sequencing. Using the CHISEL algorithm, we inferred allele- and haplotype-specific SCNAs from this whole-genome single-cell DNA sequencing data. Surprisingly, despite extensive structural complexity, these tumors exhibit a high degree of cell-cell homogeneity with little subclonal diversification. Longitudinal analysis of patient samples obtained at distant therapeutic timepoints (diagnosis, relapse) demonstrated remarkable conservation of SCNA profiles over tumor evolution. Phylogenetic analysis suggests that the majority of SCNAs were acquired early in the oncogenic process, with relatively few structure-altering events arising in response to therapy or during adaptation to growth in metastatic tissues. These data further support the emerging hypothesis that early catastrophic events, rather than sustained genomic instability, give rise to structural complexity, which is then preserved over long periods of tumor developmental time.Significance: Chromosomally complex tumors are often described as genomically unstable. However, determining whether complexity arises from remote time-limited events that give rise to structural alterations or a progressive accumulation of structural events in persistently unstable tumors has implications for diagnosis, biomarker assessment, mechanisms of treatment resistance, and represents a conceptual advance in our understanding of intratumoral heterogeneity and tumor evolution.

DOI: https://doi.org/10.1158/2767-9764.CRC-22-0348