bims-ectoca 2024-04-07 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024‒04‒07
ten papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Enhancing the productivity and proliferation of CHO-K1 cells by oncoprotein YAP (Yes-associated protein).
Pharmacological Agents Targeting Drug-Tolerant Persister Cells in Cancer.
Super enhancer lncRNAs: a novel hallmark in cancer.
Osteosarcoma through the Lens of Bone Development, Signaling, and Microenvironment.
DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover.
Long noncoding RNAs and their possible roles in tumorigenesis and drug resistance in cancer chemotherapy.
p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response.
Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma.
CCDC25 suppresses clear cell renal cell carcinoma progression by LATS1/YAP-mediated regulation of the hippo pathway.
Quantifying redox transcription factor dynamics as a tool to investigate redox signalling.

Appl Microbiol Biotechnol. 2024 Apr 04. 108(1): 285

Enhancing the productivity and proliferation of CHO-K1 cells by oncoprotein YAP (Yes-associated protein).

Farnaz Roshanmehr, Shahriyar Abdoli, Zahra Bazi, Maryam Jari, Majid Shahbazi.

  CHO cells are extensively employed in biological drug industry to manufacture therapeutic proteins. Nevertheless, production of biopharmaceuticals faces obstacles such as limited growth and inadequate productivity. Employing host cell engineering techniques for CHO cells serves as a valuable approach to address the constraints encountered in biologics manufacturing. Despite advancements, most techniques focus on specific genes to address individual cellular challenges. The significance of YAP, transcriptional co-activator, cannot be overstated due to its involvement in regulating organ size and tumor formation. YAP's influence extends to various cellular processes and is regulated by kinase cascade in the Hippo pathway, which phosphorylates serine residues in specific LATS recognition motifs. Activation of YAP has been observed to impact both the size and quantity of cells. This research investigates the effects of YAP5SA on proliferation, apoptosis, and productivity in CHO-K1 cells. YAP5SA, with mutations in all five LATS-target sites, is selected for its heightened activity and resistance to repression through the Hippo-LATS1/2 kinase signaling pathway. Plasmid harboring YAP5SA was transfected into EPO-CHO and the influence of YAP5SA overexpression was investigated. According to our findings, transfection of EPO-CHO cells with YAP5SA exhibited a substantial enhancement in CHO cell productivity, resulting in a 3-fold increase in total protein and EPO, as well as a 1.5-fold increase in specific productivity. Additionally, it significantly contributes in augmenting viability, size, and proliferation. Overall, the findings of this study exemplify the potential of utilizing YAP5SA to impact particular cellular mechanisms, thereby presenting an avenue for customizing cells to fulfill production demands. KEY POINTS: • YAP5SA in CHO cells boosts growth, reduces apoptosis, and significantly improves productivity. • YAP5SA regulates genes involved in proliferation, survival, and mTOR activation. • YAP5SA increases productivity by improving cell cycle, c-MYC expression, and mTOR pathway.

Keywords:  Chinese hamster ovary (CHO) cells; Hippo pathway; Phospho-mutant YAP5SA; Productivity; YAP (Yes-associated protein)

DOI:  https://doi.org/10.1007/s00253-024-13122-5
Pharmacol Res. 2024 Apr 01. pii: S1043-6618(24)00107-5. [Epub ahead of print] 107163

Pharmacological Agents Targeting Drug-Tolerant Persister Cells in Cancer.

Yu-Chi Chen, Krishna Gowda, Shantu Amin, Todd D Schell, Arun K Sharma, Gavin P Robertson.

  Current cancer therapy can be effective, but the development of drug resistant disease is the usual outcome. These drugs can eliminate most of the tumor burden but often fail to eliminate the rare, "Drug Tolerant Persister" (DTP) cell subpopulations in residual tumors, which can be referred to as "Persister" cells. Therefore, novel therapeutic agents specifically targeting or preventing the development of drug-resistant tumors mediated by the remaining persister cells subpopulations are needed. Since approximately ninety percent of cancer-related deaths occur because of the eventual development of drug resistance, identifying, and dissecting the biology of the persister cells is essential for the creation of drugs to target them. While there remains uncertainty surrounding all the markers identifying DTP cells in the literature, this review summarizes the drugs and therapeutic approaches that are available to target the persister cell subpopulations expressing the cellular markers ATP-binding cassette sub-family B member 5 (ABCB5), CD133, CD271, Lysine-specific histone demethylase 5 (KDM5), and aldehyde dehydrogenase (ALDH). Persister cells expressing these markers were selected as the focus of this review because they have been found on cells surviving following drug treatments that promote recurrent drug resistant cancer and are associated with stem cell-like properties, including self-renewal, differentiation, and resistance to therapy. The limitations and obstacles facing the development of agents targeting these DTP cell subpopulations are detailed, with discussion of potential solutions and current research areas needing further exploration.

Keywords:  Persister cancer cells; cancer therapy; drug resistance

DOI:  https://doi.org/10.1016/j.phrs.2024.107163
Cell Commun Signal. 2024 Apr 02. 22(1): 207

Super enhancer lncRNAs: a novel hallmark in cancer.

Ping Song, Rongyan Han, Fan Yang.

  Super enhancers (SEs) consist of clusters of enhancers, harboring an unusually high density of transcription factors, mediator coactivators and epigenetic modifications. SEs play a crucial role in the maintenance of cancer cell identity and promoting oncogenic transcription. Super enhancer lncRNAs (SE-lncRNAs) refer to either transcript from SEs locus or interact with SEs, whose transcriptional activity is highly dependent on SEs. Moreover, these SE-lncRNAs can interact with their associated enhancer regions in cis and modulate the expression of oncogenes or key signal pathways in cancers. Inhibition of SEs would be a promising therapy for cancer. In this review, we summarize the research of SE-lncRNAs in different kinds of cancers so far and decode the mechanism of SE-lncRNAs in carcinogenesis to provide novel ideas for the cancer therapy.

Keywords:  BRD4; CDK; Cancer; SE-lncRNA; Super enhancer

DOI:  https://doi.org/10.1186/s12964-024-01599-6
Cold Spring Harb Perspect Med. 2024 Apr 02. pii: a041635. [Epub ahead of print]

Osteosarcoma through the Lens of Bone Development, Signaling, and Microenvironment.

Elizabeth P Young, Amanda E Marinoff, Eunice Lopez-Fuentes, E Alejandro Sweet-Cordero.

In this work, we review the multifaceted connections between osteosarcoma (OS) biology and normal bone development. We summarize and critically analyze existing research, highlighting key areas that merit further exploration. The review addresses several topics in OS biology and their interplay with normal bone development processes, including OS cell of origin, genomics, tumor microenvironment, and metastasis. We examine the potential cellular origins of OS and how their roles in normal bone growth may contribute to OS pathogenesis. We survey the genomic landscape of OS, highlighting the developmental roles of genes frequently altered in OS. We then discuss the OS microenvironment, emphasizing the transformation of the bone niche in OS to facilitate tumor growth and metastasis. The role of stromal and immune cells is examined, including their impact on tumor progression and therapeutic response. We further provide insights into potential development-informed opportunities for novel therapeutic strategies.

DOI: https://doi.org/10.1101/cshperspect.a041635
J Cell Sci. 2024 Apr 02. pii: jcs.261687. [Epub ahead of print]

DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover.

Aukie Hooglugt, Miesje M van der Stoel, Apeksha Shapeti, Beau F Neep, Annett de Haan, Hans van Oosterwyck, Reinier A Boon, Stephan Huveneers.

  Angiogenesis is a tightly controlled dynamic process demanding a delicate equilibrium between pro-angiogenic signals and factors that promote vascular stability. The spatiotemporal activation of the transcriptional co-factors YAP/TAZ is crucial to allow for efficient collective endothelial migration in angiogenesis. The focal adhesion protein Deleted-in-liver-cancer-1 (DLC1) was recently described as a transcriptional downstream target of YAP/TAZ in endothelial cells. In this study, we uncover a negative feedback loop between DLC1 expression and YAP activity during collective migration and sprouting angiogenesis. In particular, our study demonstrates that signaling via the RhoGAP domain of DLC1 reduces YAP's nuclear localization and its transcriptional activity. Moreover, the RhoGAP activity of DLC1 is essential for YAP-mediated cellular processes, including the regulation of focal adhesion turnover, traction forces, and sprouting angiogenesis. We show that DLC1 restricts intracellular cytoskeletal tension by inhibiting Rho signaling at the basal adhesion plane, consequently reducing nuclear YAP localization. Collectively, these findings underscore the significance of DLC1 expression levels and its function in mitigating intracellular tension as a pivotal mechanotransductive feedback mechanism that finely tunes YAP activity throughout the process of sprouting angiogenesis.

Keywords:  Angiogenesis; DLC1; Endothelium; Focal adhesion; Force; Integrin; Mechanotransduction; Migration; Rho GTPase; Stiffness; YAP/TAZ

DOI:  https://doi.org/10.1242/jcs.261687
Nucleosides Nucleotides Nucleic Acids. 2024 Apr 04. 1-15

Long noncoding RNAs and their possible roles in tumorigenesis and drug resistance in cancer chemotherapy.

Ehsan Sayed Ali, Ali Erdinç Yalın, Serap Yalın.

  Cancer is still one of the most important diseases that have a high mortality rate around the world. The management of cancer involves many procedures, which include surgery, radiotherapy, and chemotherapy. Drug resistance in cancer chemotherapy is considered one of the most important problems in clinical oncology. A good understanding of the tumorigenesis process and the mechanisms of developing chemotherapy resistance in cancer cells will help achieve significant advances in cancer treatment protocols. In recent years, there has been an increasing interest in long noncoding RNAs (lncRNAs). LncRNAs are no longer just a transcriptional noise, and many investigations proved their possible roles in regulating mandatory cellular functions. A lot of newly published studies confirmed the implication of lncRNAs in the tumor formation process and the multiple drug resistance in cancer chemotherapy. The main aim of this review is to focus on the lncRNAs' functions in the cell, their possible roles in the tumor formation process, and their roles in the development of chemotherapy resistance in different cancer cells.

Keywords:  LncRNAs; chemotherapy resistance; tumor formation process

DOI:  https://doi.org/10.1080/15257770.2024.2336210
Nat Commun. 2024 Apr 01. 15(1): 2821

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response.

François Serra, Andrea Nieto-Aliseda, Lucía Fanlo-Escudero, Llorenç Rovirosa, Mónica Cabrera-Pasadas, Aleksey Lazarenkov, Blanca Urmeneta, Alvaro Alcalde-Merino, Emanuele M Nola, Andrei L Okorokov, Peter Fraser, Mariona Graupera, Sandra D Castillo, Jose L Sardina, Alfonso Valencia, Biola M Javierre.

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.

DOI: https://doi.org/10.1038/s41467-024-46666-1
Front Genet. 2024 ;15 1303404

Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma.

James E Jacobs, Lara Davis, Shannon McWeeney.

  Introduction: The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking.Materials and Methods: We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes.
Results: Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype.
Discussion: Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.

Keywords:  MYC-overexpression; differential gene expression; genomic instability; nuclear pore complex; osteosarcoma; single nucleotide variants

DOI:  https://doi.org/10.3389/fgene.2024.1303404
Cancer Cell Int. 2024 Apr 03. 24(1): 124

CCDC25 suppresses clear cell renal cell carcinoma progression by LATS1/YAP-mediated regulation of the hippo pathway.

Hongpei Tan, Jiahao Liu, Yanan Li, Ze Mi, Baiying Liu, Pengfei Rong.

  BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent renal cancers, and the molecular mechanisms underlying its progression are still not fully understood. The expression of CCDC25, a notably underexpressed gene in many tumors, has been understudied in ccRCC. This research aims to explore the role of CCDC25 in ccRCC's clinical outcomes and uncover the molecular pathways influenced by it.METHODS: A multi-tiered approach was adopted involving bioinformatic analysis, tissue sample evaluation, in vitro and in vivo experiments. CCDC25 expression levels in tumor vs. normal tissues were quantified using Western blot and immunofluorescence studies. Cell proliferation and migration were analyzed using CCK8, EDU, Transwell assays, and wound healing assays. RNA sequencing was performed to elucidate the molecular pathways affected, followed by detailed protein-protein interaction studies and mouse xenograft models.
RESULTS: CCDC25 was predominantly underexpressed in ccRCC tumors and associated with advanced clinical stages and poor prognosis. Overexpression of CCDC25 in renal cancer cell lines resulted in reduced proliferation and migration. RNA sequencing revealed significant alterations in the Hippo pathway. Overexpression of CCDC25 inhibited the expression of downstream Hippo pathway proteins ITGA3 and CCND1 and promoted YAP phosphorylation. Mechanistic studies showed that CCDC25 interacts with YAP and influences YAP phosphorylation through LATS1. In vivo, CCDC25 overexpression inhibited tumor growth and promoted apoptosis.
CONCLUSION: CCDC25 acts as a potential tumor suppressor in ccRCC by inhibiting cell proliferation and migration, potentially through regulating the Hippo signaling pathway. These findings highlight the potential of CCDC25 as a therapeutic target in ccRCC treatment.

Keywords:  CCDC25; Clear cell renal cell carcinoma; Hippo; Prognosis; YAP (Yes-associated protein)

DOI:  https://doi.org/10.1186/s12935-024-03318-0
Free Radic Biol Med. 2024 Apr 02. pii: S0891-5849(24)00169-2. [Epub ahead of print]218 16-25

Quantifying redox transcription factor dynamics as a tool to investigate redox signalling.

Diane J Lind, Kelisa C Naidoo, Lewis E Tomalin, Johann M Rohwer, Elizabeth A Veal, Ché S Pillay.

A critical feature of the cellular antioxidant response is the induction of gene expression by redox-sensitive transcription factors. In many cells, activating these transcription factors is a dynamic process involving multiple redox steps, but it is unclear how these dynamics should be measured. Here, we show how the dynamic profile of the Schizosaccharomyces pombe Pap1 transcription factor is quantifiable by three parameters: signal amplitude, signal time and signal duration. In response to increasing hydrogen peroxide concentrations, the Pap1 amplitude decreased while the signal time and duration showed saturable increases. In co-response plots, these parameters showed a complex, non-linear relationship to the mRNA levels of four Pap1-regulated genes. We also demonstrate that hydrogen peroxide and tert-butyl hydroperoxide trigger quantifiably distinct Pap1 activation profiles and transcriptional responses. Based on these findings, we propose that different oxidants and oxidant concentrations modulate the Pap1 dynamic profile, leading to specific transcriptional responses. We further show how the effect of combination and pre-exposure stresses on Pap1 activation dynamics can be quantified using this approach. This method is therefore a valuable addition to the redox signalling toolbox that may illuminate the role of dynamics in determining appropriate responses to oxidative stress.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.04.004