bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024–08–25
ten papers selected by
Ankita Daiya, OneCell Diagnostics Inc.
  1. Retinoic acid-induced protein 14 links mechanical forces to Hippo signaling.
  2. HDAC6 inhibition disrupts HDAC6-P300 interaction reshaping the cancer chromatin landscape.
  3. TRIM44 enhances autophagy via SQSTM1 oligomerization in response to oxidative stress.
  4. Stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and verteporfin for glioblastoma therapy.
  5. Advancing cellular insights: Super-resolution STORM imaging of cytoskeletal structures in human stem and cancer cells.
  6. Heterogeneous flexibility can contribute to chromatin segregation in the cell nucleus.
  7. A pan-cancer screen identifies drug combination benefit in cancer cell lines at the individual and population level.
  8. From rest to repair: Safeguarding genomic integrity in quiescent cells.
  9. Repurposing of known drugs from multiple libraries to identify novel and potential selective inhibitors of HDAC6 via in silico approach and molecular modeling.
  10. A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells.
  1. EMBO Rep. 2024 Aug 19.
    Retinoic acid-induced protein 14 links mechanical forces to Hippo signaling.
    Wonyoung Jeong, Hyeryun Kwon, Sang Ki Park, In-Seob Lee, Eek-Hoon Jho.
      Cells sense and respond to various mechanical forces from the extracellular matrix primarily by modulating the actin cytoskeleton. Mechanical forces can be translated into biochemical signals in a process called mechanotransduction. Yes-associated protein (YAP) is an effector of Hippo signaling and a mediator of mechanotransduction, but how mechanical forces regulate Hippo signaling is still an open question. We propose that retinoic acid-induced protein 14 (RAI14) responds to mechanical forces and regulates Hippo signaling. RAI14 positively regulates the activity of YAP. RAI14 interacts with NF2, a key component of the Hippo pathway, and the interaction occurs on filamentous actin. When mechanical forces are kept low in cells, NF2 dissociates from RAI14 and filamentous actin, resulting in increased interactions with LATS1 and activation of the Hippo pathway. Clinical data show that tissue stiffness and expression of RAI14 and YAP are upregulated in tumor tissues and that RAI14 is strongly associated with adverse outcome in patients with gastric cancer. Our data suggest that RAI14 links mechanotransduction with Hippo signaling and mediates Hippo-related biological functions such as cancer progression.
    Keywords:  Gastric Cancer; Hippo Signaling; Mechanotransduction; RAI14
    DOI:  https://doi.org/10.1038/s44319-024-00228-0
  2. Clin Epigenetics. 2024 Aug 18. 16(1): 109
    HDAC6 inhibition disrupts HDAC6-P300 interaction reshaping the cancer chromatin landscape.
    Michela Gottardi Zamperla, Barbara Illi, Veronica Barbi, Chiara Cencioni, Daniele Santoni, Stella Gagliardi, Maria Garofalo, Gabriele Antonio Zingale, Irene Pandino, Diego Sbardella, Lina Cipolla, Simone Sabbioneda, Antonella Farsetti, Chiara Ripamonti, Gianluca Fossati, Christian Steinkühler, Carlo Gaetano, Sandra Atlante.
       BACKGROUND: Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells.
    METHODS AND RESULTS: We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival.
    CONCLUSIONS: Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.
    Keywords:  Apoptosis; Cancer; Cell cycle; Deacetylase inhibitors; HAT; HDAC; Histone acetylation; Proliferation; Tumorigenesis
    DOI:  https://doi.org/10.1186/s13148-024-01725-8
  3. Sci Rep. 2024 08 16. 14(1): 18974
    TRIM44 enhances autophagy via SQSTM1 oligomerization in response to oxidative stress.
    Yuqin Wang, Lin Lyu, Trung Vu, Nami McCarty.
      The deubiquitinase tripartite motif containing 44 (TRIM44) plays a critical role in linking the proteotoxic stress response with autophagic degradation, which is significant in the context of cancer and neurological diseases. Although TRIM44 is recognized as a prognostic marker in various cancers, the complex molecular mechanisms through which it facilitates autophagic degradation, particularly under oxidative stress conditions, have not been fully explored. In this study, we demonstrate that TRIM44 significantly enhances autophagy in response to oxidative stress, reducing cytotoxicity in cancer cells treated with arsenic trioxide. Our research emphasizes the critical role of the posttranslational modification of sequestosome-1 (SQSTM1) and its importance in improving sequestration during autophagic degradation under oxidative stress. We found that TRIM44 notably promotes SQSTM1 oligomerization in both PB1 domain-dependent and oxidation-dependent manners. Furthermore, TRIM44 amplifies the interaction between protein kinase A and oligomerized SQSTM1, leading to enhanced phosphorylation of SQSTM1 at S349. This phosphorylation event activates NFE2L2, a key transcription factor in the oxidative stress response, highlighting the importance of TRIM44 in modulating SQSTM1-mediated autophagy. Our findings support that TRIM44 plays pivotal roles in regulating autophagic sensitivity to oxidative stress, with implications for cancer, aging, aging-associated diseases, and neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41598-024-67832-x
  4. J Nanobiotechnology. 2024 Aug 20. 22(1): 495
    Stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and verteporfin for glioblastoma therapy.
    Ji Qi, Long Zhang, Zhongyu Ren, Yi Yuan, Jiahao Yu, Yining Zhang, Linbo Gu, Xu Wang, Yan Wang, Haoyue Xu, Rutong Yu, Xiuping Zhou.
       BACKGROUND: The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree.
    RESULTS: In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent blood‒brain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects.
    CONCLUSION: Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.
    Keywords:  Glioblastoma; Nanomedicine; Polymetronidazole; VP; siYAP
    DOI:  https://doi.org/10.1186/s12951-024-02776-y
  5. Biochem Biophys Rep. 2024 Sep;39 101798
    Advancing cellular insights: Super-resolution STORM imaging of cytoskeletal structures in human stem and cancer cells.
    Anupam Bharadwaj, Amalesh Kumar, Sam Padalumavunkal Mathew, Rumela Mitra, Jina Bhattacharyya, Bithiah Grace Jaganathan, Bosanta R Boruah.
      Fluorescence microscopy is an important tool for cell biology and cancer research. Present-day approach of implementing advanced optical microscopy methods combined with immunofluorescence labelling of specific proteins in cells is now able to deliver optical super-resolution up to ∼25 nm. Here we perform super-resolved imaging using standard immunostaining protocol combined with easy stochastic optical reconstruction microscopy (easySTORM) to observe structural differences of two cytoskeleton elements, actin and tubulin in three different cell types namely human bone marrow-derived mesenchymal stem cells (MSCs), human glioblastoma (U87MG) and breast cancer (MDAMB-231) cells. The average width of the actin bundle obtained from STORM images of stem cells is observed to be larger than the same for U87MG and MDAMB-231 cells. No significant difference is however noticed in the width of the tubulin within the same cells. We also study the functional effect on the 2D migration potential of MDAMB-231 cells silenced for NICD1 and β-catenin. Although similar migration speed is observed for cells with the above two conditions compared to their control cells, easySTORM images show that widths of the actin in MDAMB-231 cells in β-catenin silenced is significantly lower than the same in control cells. Such minute differences however are not observable in widefield images. The outcome of our easySTORM investigation should benefit the researchers carrying out detailed investigations of the cellular structure and potential therapeutic applications.
    Keywords:  Breast cancer; Optical super-resolution microscopy; Stochastic optical reconstruction microscopy; Tubulin; actin cytoskeleton; β-catenin
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101798
  6. Phys Rev E. 2024 Jul;110(1-1): 014403
    Heterogeneous flexibility can contribute to chromatin segregation in the cell nucleus.
    Martin Girard, Monica Olvera de la Cruz, John F Marko, Aykut Erbaş.
      The highly and slightly condensed forms of chromatin, heterochromatin and euchromatin, respectively, segregate in the cell nucleus. Heterochromatin is more abundant in the nucleus periphery. Here we study the mechanism of heterochromatin segregation by modeling interphase chromosomes as diblock ring copolymers confined in a rigid spherical shell using molecular dynamics simulations. In our model, heterochromatin and euchromatin are distinguished by their bending stiffnesses only, while an interaction potential between the spherical shell and chromatin is used to model lamin-associated proteins. Our simulations indicate that in the absence of attractive interactions between the nuclear shell and the chromatin, most heterochromatin segregates towards the nuclear interior due to the depletion of less flexible heterochromatin segments from the nuclear periphery. This inverted chromatin distribution,which is opposite to the conventional case with heterochromatin dominating at the periphery, is in accord with experimental observations in rod cells. This "inversion" is also found to be independent of the heterochromatin concentration and chromosome number. The chromatin distribution at the periphery found in vivo can be recovered by further increasing the bending stiffness of heterochromatin segments or by turning on attractive interactions between the nuclear shell and heterochromatin. Our results indicate that the bending stiffness of chromatin could be a contributor to chromosome organization along with differential effects of HP1α-driven phase segregation and of loop extruders and interactions with the nuclear envelope and topological constraints.
    DOI:  https://doi.org/10.1103/PhysRevE.110.014403
  7. Cell Rep Med. 2024 Aug 20. pii: S2666-3791(24)00408-7. [Epub ahead of print]5(8): 101687
    A pan-cancer screen identifies drug combination benefit in cancer cell lines at the individual and population level.
    Daniel J Vis, Patricia Jaaks, Nanne Aben, Elizabeth A Coker, Syd Barthorpe, Alexandra Beck, Caitlin Hall, James Hall, Howard Lightfoot, Ermira Lleshi, Tatiana Mironenko, Laura Richardson, Charlotte Tolley, Mathew J Garnett, Lodewyk F A Wessels.
      Combining drugs can enhance their clinical efficacy, but the number of possible combinations and inter-tumor heterogeneity make identifying effective combinations challenging, while existing approaches often overlook clinically relevant activity. We screen one of the largest cell line panels (N = 757) with 51 clinically relevant combinations and identify responses at the level of individual cell lines and tissue populations. We establish three response classes to model cellular effects beyond monotherapy: synergy, Bliss additivity, and independent drug action (IDA). Synergy is rare (11% of responses) and frequently efficacious (>50% viability reduction), whereas Bliss and IDA are more frequent but less frequently efficacious. We introduce "efficacious combination benefit" (ECB) to describe high-efficacy responses classified as either synergy, Bliss, or IDA. We identify ECB biomarkers in vitro and show that ECB predicts response in patient-derived xenografts better than synergy alone. Our work here provides a valuable resource and framework for preclinical evaluation and the development of combination treatments.
    Keywords:  Bliss; cell lines; combination benefit; drug combinations; drug efficacy; drug potency; high-throughput screening; independent drug action; synergy
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101687
  8. DNA Repair (Amst). 2024 Aug 20. pii: S1568-7864(24)00128-9. [Epub ahead of print]142 103752
    From rest to repair: Safeguarding genomic integrity in quiescent cells.
    Chin Wei Brian Leung, Jacob Wall, Fumiko Esashi.
      Quiescence is an important non-pathological state in which cells pause cell cycle progression temporarily, sometimes for decades, until they receive appropriate proliferative stimuli. Quiescent cells make up a significant proportion of the body, and maintaining genomic integrity during quiescence is crucial for tissue structure and function. While cells in quiescence are spared from DNA damage associated with DNA replication or mitosis, they are still exposed to various sources of endogenous DNA damage, including those induced by normal transcription and metabolism. As such, it is vital that cells retain their capacity to effectively repair lesions that may occur and return to the cell cycle without losing their cellular properties. Notably, while DNA repair pathways are often found to be downregulated in quiescent cells, emerging evidence suggests the presence of active or differentially regulated repair mechanisms. This review aims to provide a current understanding of DNA repair processes during quiescence in mammalian systems and sheds light on the potential pathological consequences of inefficient or inaccurate repair in quiescent cells.
    Keywords:  DNA repair; Genome stability; Metabolism; Quiescence; Transcription
    DOI:  https://doi.org/10.1016/j.dnarep.2024.103752
  9. Heliyon. 2024 Aug 15. 10(15): e35020
    Repurposing of known drugs from multiple libraries to identify novel and potential selective inhibitors of HDAC6 via in silico approach and molecular modeling.
    Naz Mina Mert, Buse Erdogan, Kemal Yelekçi.
      Histone deacetylase 6 (HDAC6, Class IIb) is a promising target for anticancer drugs. So far, few nonselective HDAC inhibitors have received regulatory approval as anticancer agents. However, they are associated with cell toxicity. Thus, isoform-selective inhibitors may be desirable. Here, we conducted structure-based virtual screening of multiple libraries containing a total of 2,250,135 compounds against HDAC6. The top hits with good docking scores and potential selectivity over HDAC10 (Class IIb) were submitted to 100 ns molecular dynamics simulation to monitor their dynamic behaviors and stability in the binding pockets of these enzymes. Furthermore, the drug-likeness and ADMET properties of these hits were estimated computationally. Four diverse compounds from different sources, including NCI and ZINC databases (BDH33926500, CID667061, Cromolyn, and ZINC000103531486), show potential selectivity for HDAC6.
    Keywords:  Cancer; Docking; HDAC6; HDAC6 selective inhibitors; In silico screening; M.D. simulation
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e35020
  10. Cancer Sci. 2024 Aug 18.
    A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells.
    Hiroki Hikasa, Kohichi Kawahara, Masako Inui, Yukichika Yasuki, Keita Yamashita, Kohei Otsubo, Shojiro Kitajima, Miki Nishio, Kazunari Arima, Motoyoshi Endo, Masanori Taira, Akira Suzuki.
      The activation of yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) has been implicated in both regeneration and tumorigenesis, thus representing a double-edged sword in tissue homeostasis. However, how the activity of YAP1/TAZ is regulated or what leads to its dysregulation in these processes remains unknown. To explore the upstream stimuli modulating the cellular activity of YAP1/TAZ, we developed a highly sensitive YAP1/TAZ/TEAD-responsive DNA element (YRE) and incorporated it into a lentivirus-based reporter cell system to allow for sensitive and specific monitoring of the endogenous activity of YAP1/TAZ in terms of luciferase activity in vitro and Venus fluorescence in vivo. Furthermore, by replacing YRE with TCF- and NF-κB-binding DNA elements, we demonstrated the applicability of this reporter system to other pathways such as Wnt/β-catenin/TCF- and IL-1β/NF-κB-mediated signaling, respectively. The practicality of this system was evaluated by performing cell-based reporter screening of a chemical compound library consisting of 364 known inhibitors, using reporter-introduced cells capable of quantifying YAP1/TAZ- and β-catenin-mediated transcription activities, which led to the identification of multiple inhibitors, including previously known as well as novel modulators of these signaling pathways. We further confirmed that novel YAP1/TAZ modulators, such as potassium ionophores, Janus kinase inhibitors, platelet-derived growth factor receptor inhibitors, and genotoxic stress inducers, alter the protein level or phosphorylation of endogenous YAP1/TAZ and the expression of their target genes. Thus, this reporter system provides a powerful tool to monitor endogenous signaling activities of interest (even in living cells) and search for modulators in various cellular contexts.
    Keywords:  Hippo‐YAP1/TAZ pathway; YAP1/TAZ modulators; cell‐based screening; highly sensitive reporter system; lentivirus
    DOI:  https://doi.org/10.1111/cas.16316
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