bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒03‒12
seventeen papers selected by
Ankita Daiya
BITS Pilani
  1. Non-hippo kinases: indispensable roles in YAP/TAZ signaling and implications in cancer therapy.
  2. 4D epigenomics: deciphering the coupling between genome folding and epigenomic regulation with biophysical modeling.
  3. Contribution of Mitochondrial Activity to Doxorubicin-Resistance in Osteosarcoma Cells.
  4. Histone Modifications Represent a Key Epigenetic Feature of Epithelial-to-Mesenchyme Transition in Pancreatic Cancer.
  5. Repurposing of triamterene as a histone deacetylase inhibitor to overcome cisplatin resistance in lung cancer treatment.
  6. Piperine improves the sensitivity of osteosarcoma cells to doxorubicin by inducing apoptosis and inhibiting the PI3K/AKT/GSK-3β pathway.
  7. Histone Deacetylases (HDACs): Promising Biomarkers and Potential Therapeutic Targets in Thymic Epithelial Tumors.
  8. Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells.
  9. Mechanobiology of cancer cell responsiveness to chemotherapy and immunotherapy: mechanistic insights and biomaterial platforms.
  10. Molecular features and predictive models identify the most lethal subtype and a therapeutic target for osteosarcoma.
  11. Pan-Cancer Analysis Reveals Functional Similarity of Three lncRNAs across Multiple Tumors.
  12. Targeting GPX4 in human cancer: Implications of ferroptosis induction for tackling cancer resilience.
  13. NFIXing Cancer: The Role of NFIX in Oxidative Stress Response and Cell Fate.
  14. Indirect bilirubin impairs invasion of osteosarcoma cells via inhibiting the PI3K/AKT/MMP-2 signaling pathway by suppressing intracellular ROS.
  15. Lipophilic Statins Inhibit YAP Nuclear Localization, Coactivator Activity, and Migration in Response to Ligation of HLA Class I Molecules in Endothelial Cells: Role of YAP Multisite Phosphorylation.
  16. Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression.
  17. RUNX3 Meets the Ubiquitin-Proteasome System in Cancer.
  1. Mol Biol Rep. 2023 Mar 06.
    Non-hippo kinases: indispensable roles in YAP/TAZ signaling and implications in cancer therapy.
    Jun Zhu, Tiantian Wu, Qiong Lin.
      The transcriptional co-activators Yes-associated protein (YAP) and PDZ-binding domain (TAZ) are the known downstream effectors of the Hippo kinase cascade. YAP/TAZ have been shown to play important roles in cellular growth and differentiation, tissue development and carcinogenesis. Recent studies have found that, in addition to the Hippo kinase cascade, multiple non-Hippo kinases also regulate the YAP/TAZ cellular signaling and produce important effects on cellular functions, particularly on tumorigenesis and progression. In this article, we will review the multifaceted regulation of the YAP/TAZ signaling by the non-Hippo kinases and discuss the potential application of the non-Hippo kinase-regulated YAP/TAZ signaling for cancer therapy.
    Keywords:  Cancer therapy; Kinase inhibitors; Non-hippo kinases; YAP/TAZ
    DOI:  https://doi.org/10.1007/s11033-023-08329-0
  2. Curr Opin Genet Dev. 2023 Mar 07. pii: S0959-437X(23)00013-8. [Epub ahead of print]79 102033
    4D epigenomics: deciphering the coupling between genome folding and epigenomic regulation with biophysical modeling.
    Amith Z Abdulla, Hossein Salari, Maxime M C Tortora, Cédric Vaillant, Daniel Jost.
      Recent experimental observations suggest a strong coupling between the 3D nuclear chromosome organization and epigenomics. However, the mechanistic and functional bases of such interplay remain elusive. In this review, we describe how biophysical modeling has been instrumental in characterizing how genome folding may impact the formation of epigenomic domains and, conversely, how epigenomic marks may affect chromosome conformation. Finally, we discuss how this mutual feedback loop between chromatin organization and epigenome regulation, via the formation of physicochemical nanoreactors, may represent a key functional role of 3D compartmentalization in the assembly and maintenance of stable - but yet plastic - epigenomic landscapes.
    DOI:  https://doi.org/10.1016/j.gde.2023.102033
  3. Cancers (Basel). 2023 Feb 21. pii: 1370. [Epub ahead of print]15(5):
    Contribution of Mitochondrial Activity to Doxorubicin-Resistance in Osteosarcoma Cells.
    Isabella Giacomini, Margherita Cortini, Mattia Tinazzi, Nicola Baldini, Veronica Cocetta, Eugenio Ragazzi, Sofia Avnet, Monica Montopoli.
      Osteosarcoma is considered the most common bone tumor affecting children and young adults. The standard of care is chemotherapy; however, the onset of drug resistance still jeopardizes osteosarcoma patients, thus making it necessary to conduct a thorough investigation of the possible mechanisms behind this phenomenon. In the last decades, metabolic rewiring of cancer cells has been proposed as a cause of chemotherapy resistance. Our aim was to compare the mitochondrial phenotype of sensitive osteosarcoma cells (HOS and MG-63) versus their clones when continuously exposed to doxorubicin (resistant cells) and identify alterations exploitable for pharmacological approaches to overcome chemotherapy resistance. Compared with sensitive cells, doxorubicin-resistant clones showed sustained viability with less oxygen-dependent metabolisms, and significantly reduced mitochondrial membrane potential, mitochondrial mass, and ROS production. In addition, we found reduced expression of TFAM gene generally associated with mitochondrial biogenesis. Finally, combined treatment of resistant osteosarcoma cells with doxorubicin and quercetin, a known inducer of mitochondrial biogenesis, re-sensitizes the doxorubicin effect in resistant cells. Despite further investigations being needed, these results pave the way for the use of mitochondrial inducers as a promising strategy to re-sensitize doxorubicin cytotoxicity in patients who do not respond to therapy or reduce doxorubicin side effects.
    Keywords:  cancer; chemotherapy; doxorubicin; drug resistance; metabolism; mitochondria; osteosarcoma; targeting mitochondrial alterations
    DOI:  https://doi.org/10.3390/cancers15051370
  4. Int J Mol Sci. 2023 Mar 02. pii: 4820. [Epub ahead of print]24(5):
    Histone Modifications Represent a Key Epigenetic Feature of Epithelial-to-Mesenchyme Transition in Pancreatic Cancer.
    Ying Xu, Qing Zhu.
      Pancreatic cancer is one of the most lethal malignant diseases due to its high invasiveness, early metastatic properties, rapid disease progression, and typically late diagnosis. Notably, the capacity for pancreatic cancer cells to undergo epithelial-mesenchymal transition (EMT) is key to their tumorigenic and metastatic potential, and is a feature that can explain the therapeutic resistance of such cancers to treatment. Epigenetic modifications are a central molecular feature of EMT, for which histone modifications are most prevalent. The modification of histones is a dynamic process typically carried out by pairs of reverse catalytic enzymes, and the functions of these enzymes are increasingly relevant to our improved understanding of cancer. In this review, we discuss the mechanisms through which histone-modifying enzymes regulate EMT in pancreatic cancer.
    Keywords:  epigenetics; epithelial-to-mesenchymal transition; histone modification; pancreatic cancer; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3390/ijms24054820
  5. J Cancer Res Clin Oncol. 2023 Mar 11.
    Repurposing of triamterene as a histone deacetylase inhibitor to overcome cisplatin resistance in lung cancer treatment.
    Kenneth K W To, Ka M Cheung, William C S Cho.
      PURPOSE: Cisplatin is the core chemotherapeutic drug used for first-line treatment of advanced non-small cell lung cancer (NSCLC). However, drug resistance is severely hindering its clinical efficacy. This study investigated the circumvention of cisplatin resistance by repurposing non-oncology drugs with putative histone deacetylase (HDAC) inhibitory effect.METHODS: A few clinically approved drugs were identified by a computational drug repurposing tool called "DRUGSURV" and evaluated for HDAC inhibition. Triamterene, originally indicated as a diuretic, was chosen for further investigation in pairs of parental and cisplatin-resistant NSCLC cell lines. Sulforhodamine B assay was used to evaluate cell proliferation. Western blot analysis was performed to examine histone acetylation. Flow cytometry was used to examine apoptosis and cell cycle effects. Chromatin immunoprecipitation was conducted to investigate the interaction of transcription factors to the promoter of genes regulating cisplatin uptake and cell cycle progression. The circumvention of cisplatin resistance by triamterene was further verified in a patient-derived tumor xenograft (PDX) from a cisplatin-refractory NSCLC patient.
    RESULTS: Triamterene was found to inhibit HDACs. It was shown to enhance cellular cisplatin accumulation and potentiate cisplatin-induced cell cycle arrest, DNA damage, and apoptosis. Mechanistically, triamterene was found to induce histone acetylation in chromatin, thereby reducing the association of HDAC1 but promoting the interaction of Sp1 with the gene promoter of hCTR1 and p21. Triamterene was further shown to potentiate the anti-cancer effect of cisplatin in cisplatin-resistant PDX in vivo.
    CONCLUSION: The findings advocate further clinical evaluation of the repurposing use of triamterene to overcome cisplatin resistance.
    Keywords:  Cisplatin; Histone deacetylases; Non-small cell lung cancer; Repurposing; Triamterene
    DOI:  https://doi.org/10.1007/s00432-023-04641-1
  6. J Orthop Surg Res. 2023 Mar 09. 18(1): 180
    Piperine improves the sensitivity of osteosarcoma cells to doxorubicin by inducing apoptosis and inhibiting the PI3K/AKT/GSK-3β pathway.
    Yubin Qi, Lin Yao, Jianke Liu, Wen Wang.
      BACKGROUND: Osteosarcoma is a primary bone malignancy associated with the highest incidence rate. Chemotherapy for osteosarcoma has not substantially changed, and survival of patients with metastatic tumours has reached a plateau. Doxorubicin (DOX) is a broad-spectrum anti-osteosarcoma drug; however, its application is limited due to its high cardiotoxicity. Piperine (PIP) has been verified to drive certain cancer cell death and increases chemosensitivity of DOX. However, the effects of PIP in promoting the chemosensitivity of osteosarcoma to DOX have not been studied.METHODS: We examined the combined effect of PIP and DOX on U2OS and 143B osteosarcoma cells. CCK-8 assays, scratch assays, flow cytometry analysis, and western blotting were performed. Furthermore, the effect of PIP combined with DOX on osteosarcoma tumours was observed in vivo using nude mice.
    RESULTS: PIP can increase the chemosensitivity of U2OS and 143B cells to DOX. Both in vitro and in vivo results showed the dramatic inhibition of cell proliferation and tumour growth by the combined therapy group compared to monotherapy groups. Apoptosis analysis revealed that PIP augments DOX-induced cell apoptosis by upregulating BAX and P53 expression, as well as reducing Bcl-2 expression. Furthermore, PIP also attenuated the initiation of the PI3K/AKT/GSK-3β signaling pathway in osteosarcoma cells by altering the expression levels of P-AKT, P-PI3K and P-GSK3β.
    CONCLUSIONS: This study revealed for the first time that PIP can potentiate the sensitivity and cytotoxicity of DOX during osteosarcoma therapy in vitro and in vivo, which probably achieved by inhibiting the PI3K/AKT/GSK-3β signalling pathway.
    Keywords:  Doxorubicin; Osteosarcoma; PI3K/AKT/GSK3β; Piperine
    DOI:  https://doi.org/10.1186/s13018-023-03642-7
  7. Int J Mol Sci. 2023 Feb 21. pii: 4263. [Epub ahead of print]24(5):
    Histone Deacetylases (HDACs): Promising Biomarkers and Potential Therapeutic Targets in Thymic Epithelial Tumors.
    Kostas Palamaris, Luisa-Maria Tzimou, Georgia Levidou, Christos Masaoutis, Irene Theochari, Dimitra Rontogianni, Stamatios Theocharis.
      Histone deacetylases (HDACs) are core epigenetic factors, with pivotal roles in the regulation of various cellular procedures, and their deregulation is a major trait in the acquisition of malignancy properties. In this study we attempt the first comprehensive evaluation of six class I (HDAC1, HDAC2, HDAC3) and II HDACs (HDAC4, HDAC5, HDAC6) expression patterns in thymic epithelial tumors (TETs), with the aim of identifying their possible association with a number of clinicopathological parameters. Our study revealed higher positivity rates and expression levels of class I enzymes compared to class II. Sub-cellular localization and level of staining varied among the six isoforms. HDAC1 was almost exclusively restricted to the nucleus, while HDAC3 demonstrated both nuclear and cytoplasmic reactivity in the majority of examined specimens. HDAC2 expression was higher in more advanced Masaoka-Koga stages, and displayed a positive correlation with dismal prognoses. The three class II HDACs (HDAC4, HDAC5, HDAC6) exhibited similar expression patterns, with predominantly cytoplasmic staining, that was higher in epithelial rich TETs (B3, C) and more advanced tumor stages, while it was also associated with disease recurrence. Our findings could provide useful insights for the effective implementation of HDACs as biomarkers and therapeutic targets for TETs, in the setting of precision medicine.
    Keywords:  biomarker; epigenetics; histone deacetylases; prognosis; thymic carcinoma; thymic epithelial tumors
    DOI:  https://doi.org/10.3390/ijms24054263
  8. Front Oncol. 2023 ;13 1110881
    Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells.
    Hao Wang, Kun Mi.
      Cellular plasticity is a well-known dynamic feature of tumor cells that endows tumors with heterogeneity and therapeutic resistance and alters their invasion-metastasis progression, stemness, and drug sensitivity, thereby posing a major challenge to cancer therapy. It is becoming increasingly clear that endoplasmic reticulum (ER) stress is a hallmark of cancer. The dysregulated expression of ER stress sensors and the activation of downstream signaling pathways play a role in the regulation of tumor progression and cellular response to various challenges. Moreover, mounting evidence implicates ER stress in the regulation of cancer cell plasticity, including epithelial-mesenchymal plasticity, drug resistance phenotype, cancer stem cell phenotype, and vasculogenic mimicry phenotype plasticity. ER stress influences several malignant characteristics of tumor cells, including epithelial-to-mesenchymal transition (EMT), stem cell maintenance, angiogenic function, and tumor cell sensitivity to targeted therapy. The emerging links between ER stress and cancer cell plasticity that are implicated in tumor progression and chemoresistance are discussed in this review, which may aid in formulating strategies to target ER stress and cancer cell plasticity in anticancer treatments.
    Keywords:  ER stress; cancer stem cell; cellular plasticity; epithelial-mesenchymal plasticity; resistance; vasculogenic mimicry
    DOI:  https://doi.org/10.3389/fonc.2023.1110881
  9. Adv Drug Deliv Rev. 2023 Mar 06. pii: S0169-409X(23)00086-8. [Epub ahead of print] 114771
    Mechanobiology of cancer cell responsiveness to chemotherapy and immunotherapy: mechanistic insights and biomaterial platforms.
    Delaram Shakiba, Guy M Genin, Silviya P Zustiak.
      Mechanical forces are central to how cancer treatments such as chemotherapeutics and immunotherapies interact with cells and tissues. At the simplest level, electrostatic forces underlie the binding events that are critical to therapeutic function. However, a growing body of literature points to mechanical factors that also affect whether a drug or an immune cell can reach a target, and to interactions between a cell and its environment affecting therapeutic efficacy. These factors affect cell processes ranging from cytoskeletal and extracellular matrix remodeling to transduction of signals by the nucleus to metastasis of cells. This review presents and critiques the state of the art of our understanding of how mechanobiology impacts drug and immunotherapy resistance and responsiveness, and of the in vitro systems that have been of value in the discovery of these effects.
    Keywords:  chemotherapy; drug responsiveness; hydrogel; stiffness; substrate compliance
    DOI:  https://doi.org/10.1016/j.addr.2023.114771
  10. Front Oncol. 2023 ;13 1111570
    Molecular features and predictive models identify the most lethal subtype and a therapeutic target for osteosarcoma.
    Kun Zheng, Yushan Hou, Yiming Zhang, Fei Wang, Aihua Sun, Dong Yang.
      Background: Osteosarcoma is the most common primary malignant bone tumor. The existing treatment regimens remained essentially unchanged over the past 30 years; hence the prognosis has plateaued at a poor level. Precise and personalized therapy is yet to be exploited.Methods: One discovery cohort (n=98) and two validation cohorts (n=53 & n=48) were collected from public data sources. We performed a non-negative matrix factorization (NMF) method on the discovery cohort to stratify osteosarcoma. Survival analysis and transcriptomic profiling characterized each subtype. Then, a drug target was screened based on subtypes' features and hazard ratios. We also used specific siRNAs and added a cholesterol pathway inhibitor to osteosarcoma cell lines (U2OS and Saos-2) to verify the target. Moreover, PermFIT and ProMS, two support vector machine (SVM) tools, and the least absolute shrinkage and selection operator (LASSO) method, were employed to establish predictive models.
    Results: We herein divided osteosarcoma patients into four subtypes (S-I ~ S-IV). Patients of S- I were found probable to live longer. S-II was characterized by the highest immune infiltration. Cancer cells proliferated most in S-III. Notably, S-IV held the most unfavorable outcome and active cholesterol metabolism. SQLE, a rate-limiting enzyme for cholesterol biosynthesis, was identified as a potential drug target for S-IV patients. This finding was further validated in two external independent osteosarcoma cohorts. The function of SQLE to promote proliferation and migration was confirmed by cell phenotypic assays after the specific gene knockdown or addition of terbinafine, an inhibitor of SQLE. We further employed two machine learning tools based on SVM algorithms to develop a subtype diagnostic model and used the LASSO method to establish a 4-gene model for predicting prognosis. These two models were also verified in a validation cohort.
    Conclusion: The molecular classification enhanced our understanding of osteosarcoma; the novel predicting models served as robust prognostic biomarkers; the therapeutic target SQLE opened a new way for treatment. Our results served as valuable hints for future biological studies and clinical trials of osteosarcoma.
    Keywords:  SQLE; cholesterol metabolism; drug target; molecular classification; osteosarcoma; predictive model
    DOI:  https://doi.org/10.3389/fonc.2023.1111570
  11. Int J Mol Sci. 2023 Mar 01. pii: 4796. [Epub ahead of print]24(5):
    Pan-Cancer Analysis Reveals Functional Similarity of Three lncRNAs across Multiple Tumors.
    Abir Khazaal, Seid Miad Zandavi, Andrei Smolnikov, Shadma Fatima, Fatemeh Vafaee.
      Long non-coding RNAs (lncRNAs) are emerging as key regulators in many biological processes. The dysregulation of lncRNA expression has been associated with many diseases, including cancer. Mounting evidence suggests lncRNAs to be involved in cancer initiation, progression, and metastasis. Thus, understanding the functional implications of lncRNAs in tumorigenesis can aid in developing novel biomarkers and therapeutic targets. Rich cancer datasets, documenting genomic and transcriptomic alterations together with advancement in bioinformatics tools, have presented an opportunity to perform pan-cancer analyses across different cancer types. This study is aimed at conducting a pan-cancer analysis of lncRNAs by performing differential expression and functional analyses between tumor and non-neoplastic adjacent samples across eight cancer types. Among dysregulated lncRNAs, seven were shared across all cancer types. We focused on three lncRNAs, found to be consistently dysregulated among tumors. It has been observed that these three lncRNAs of interest are interacting with a wide range of genes across different tissues, yet enriching substantially similar biological processes, found to be implicated in cancer progression and proliferation.
    Keywords:  cancer; functional analysis; gene ontology; long non-coding RNA; mRNA; pan-cancer analysis
    DOI:  https://doi.org/10.3390/ijms24054796
  12. Cancer Lett. 2023 Mar 07. pii: S0304-3835(23)00070-8. [Epub ahead of print] 216119
    Targeting GPX4 in human cancer: Implications of ferroptosis induction for tackling cancer resilience.
    Jaewang Lee, Jong-Lyel Roh.
      Cancer metabolic alterations have been emphasized to protect cancer cells from cell death. The metabolic reprogramming toward a mesenchymal state makes cancer cells resistant to therapy but vulnerable to ferroptosis induction. Ferroptosis is a new form of regulated cell death based on the iron-dependent accumulation of excessive lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the core regulator of ferroptosis by detoxifying cellular lipid peroxidation using glutathione as a cofactor. GPX4 synthesis requires selenium incorporation into the selenoprotein through isopentenylation and selenocysteine tRNA maturation. GPX4 synthesis and expression can be regulated by multiple levels of its transcription, translation, posttranslational modifications, and epigenetic modifications. Targeting GPX4 in cancer may be a promising strategy for effectively inducing ferroptosis and killing therapy-resistant cancer. Several pharmacological therapeutics targeting GPX4 have been developed constantly to activate ferroptosis induction in cancer. The potential therapeutic index of GPX4 inhibitors remains to be tested with thorough examinations of their safety and adverse effects in vivo and clinical trials. Many papers have been published continuously in recent years, requiring state-of-the-art updates in targeting GPX4 in cancer. Herein, we summarize targeting the GPX4 pathway in human cancer, which leads to implications of ferroptosis induction for tackling cancer resilience.
    Keywords:  Cancer; Ferroptosis; Glutathione peroxidase 4; Lipid peroxidation; Resistance
    DOI:  https://doi.org/10.1016/j.canlet.2023.216119
  13. Int J Mol Sci. 2023 Feb 21. pii: 4293. [Epub ahead of print]24(5):
    NFIXing Cancer: The Role of NFIX in Oxidative Stress Response and Cell Fate.
    Vanessa Ribeiro, Susana G Martins, Ana Sofia Lopes, Sólveig Thorsteinsdóttir, Rita Zilhão, Ana Rita Carlos.
      NFIX, a member of the nuclear factor I (NFI) family of transcription factors, is known to be involved in muscle and central nervous system embryonic development. However, its expression in adults is limited. Similar to other developmental transcription factors, NFIX has been found to be altered in tumors, often promoting pro-tumorigenic functions, such as leading to proliferation, differentiation, and migration. However, some studies suggest that NFIX can also have a tumor suppressor role, indicating a complex and cancer-type dependent role of NFIX. This complexity may be linked to the multiple processes at play in regulating NFIX, which include transcriptional, post-transcriptional, and post-translational processes. Moreover, other features of NFIX, including its ability to interact with different NFI members to form homodimers or heterodimers, therefore allowing the transcription of different target genes, and its ability to sense oxidative stress, can also modulate its function. In this review, we examine different aspects of NFIX regulation, first in development and then in cancer, highlighting the important role of NFIX in oxidative stress and cell fate regulation in tumors. Moreover, we propose different mechanisms through which oxidative stress regulates NFIX transcription and function, underlining NFIX as a key factor for tumorigenesis.
    Keywords:  NFIX; cancer; cell fate; development; oxidative stress
    DOI:  https://doi.org/10.3390/ijms24054293
  14. J Bone Oncol. 2023 Apr;39 100472
    Indirect bilirubin impairs invasion of osteosarcoma cells via inhibiting the PI3K/AKT/MMP-2 signaling pathway by suppressing intracellular ROS.
    Xuhui Yuan, Cong Ma, Jiayu Li, Junhong Li, Ronghui Yu, Feng Cai, Gaoyang Qu, Bo Yu, Lang Liu, Duo Zeng, QuanHui Jiao, Qi Liao, Xiaobin Lv.
      Background: Osteosarcoma is most prevalently found primary malignant bone tumors, with primary metastatic patients accounting for approximately 25% of all osteosarcoma patients, yet their 5-year OS remains below 30%. Bilirubin plays a key role in oxidative stress-associated events, including malignancies, making the regulation of its serum levels a potential anti-tumor strategy. Herein, we investigated the association of osteosarcoma prognosis with serum levels of TBIL, IBIL and DBIL, and further explored the mechanisms by which bilirubin affects tumor invasion and migration.Methods: ROC curve was plotted to assess survival conditions based on the determined optimal cut-off values and the AUC. Then, Kaplan-Meier curves, along with Cox proportional hazards model, was applied for survival analysis. Inhibitory function of IBIL on the malignant properties of osteosarcoma cells was examined using the qRT-PCR, transwell assays, western blotting, and flow cytometry.
    Results: We found that, versus osteosarcoma patients with pre-operative higher IBIL (>8.9 μmol/L), those with low IBIL (≤8.9 μmol/L) had shorter OS and PFS. As indicated by the Cox proportional hazards model, pre-operative IBIL functioned as an independent prognostic factor for OS and PFS in total and gender-stratified osteosarcoma patients (P < 0.05 for all). In vitro experiments further confirmed that IBIL inhibits PI3K/AKT phosphorylation and downregulates MMP-2 expression via reducing intracellular ROS, thereby decreasing the invasion of osteosarcoma cells.
    Conclusions: IBIL may serve as an independent prognostic predictor for osteosarcoma patients. IBIL impairs invasion of osteosarcoma cells through repressing the PI3K/AKT/MMP-2 pathway by suppressing intracellular ROS, thus inhibiting its metastatic potential.
    Keywords:  AUC, area under curve; BRNP, PEGylated bilirubin nanoparticles; CCK-8, cell counting kit-8; CI, confidence interval; DBIL, direct bilirubin; DMSO, dimethyl sulfoxide; ECM, extracellular matrix; H2O2, hydrogen peroxide; HIF-1α, hypoxia inducible factor-1α; HR, hazard ratio; IBIL; IBIL, indirect bilirubin; Invasion; MDA, malondialdehyde; MMP, matrix metalloproteinase; OS, overall survival; Osteosarcoma; PFS, progression-free survival; PI3K/AKT/MMP-2; PVDF, polyvinylidene fluoride; Prognosis; ROC, receiver operative characteristic; ROS, reactive oxygen species; SD, standard deviation; SOD, superoxide dismutase; TBIL, total bilirubin; TIMP, tissue inhibitor of matrix metalloproteinase; VEGF, vascular endothelial growth factor; qRT-PCR, real-time quantitative PCR
    DOI:  https://doi.org/10.1016/j.jbo.2023.100472
  15. J Immunol. 2023 Mar 01. pii: ji2200568. [Epub ahead of print]
    Lipophilic Statins Inhibit YAP Nuclear Localization, Coactivator Activity, and Migration in Response to Ligation of HLA Class I Molecules in Endothelial Cells: Role of YAP Multisite Phosphorylation.
    Tarique Anwar, James Sinnett-Smith, Yi-Ping Jin, Elaine F Reed, Enrique Rozengurt.
      Solid-organ transplant recipients exhibiting HLA donor-specific Abs are at risk for graft loss due to chronic Ab-mediated rejection. HLA Abs bind HLA molecules expressed on the surface of endothelial cells (ECs) and induce intracellular signaling pathways, including the activation of the transcriptional coactivator yes-associated protein (YAP). In this study, we examined the impact of lipid-lowering drugs of the statin family on YAP localization, multisite phosphorylation, and transcriptional activity in human ECs. Exposure of sparse cultures of ECs to cerivastatin or simvastatin induced striking relocalization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEA domain DNA-binding transcription factor-regulated genes connective tissue growth factor and cysteine-rich angiogenic inducer 61. In dense cultures of ECs, statins prevented YAP nuclear import and expression of connective tissue growth factor and cysteine-rich angiogenic inducer 61 stimulated by the mAb W6/32 that binds HLA class I. Exposure of ECs to either cerivastatin or simvastatin completely blocked the migration of ECs stimulated by ligation of HLA class I. Exogenously supplied mevalonic acid or geranylgeraniol reversed the inhibitory effects of statins on YAP localization either in low-density ECs or high-density ECs challenged with W6/32. Mechanistically, cerivastatin increased the phosphorylation of YAP at Ser127, blunted the assembly of actin stress fiber, and inhibited YAP phosphorylation at Tyr357 in ECs. Using mutant YAP, we substantiated that YAP phosphorylation at Tyr357 is critical for YAP activation. Collectively, our results indicate that statins restrain YAP activity in EC models, thus providing a plausible mechanism underlying their beneficial effects in solid-organ transplant recipients.
    DOI:  https://doi.org/10.4049/jimmunol.2200568
  16. Sci Rep. 2023 Mar 07. 13(1): 3760
    Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression.
    Alexandra-Larisa Condurat, Sepideh Aminzadeh-Gohari, Mirjana Malnar, Nicole Schider, Leonie Opitz, Ria Thomas, Vishal Menon, Barbara Kofler, Jan Pruszak.
      Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug shown to directly inhibit YAP/TAZ activity. Our study aimed to investigate VPF's potential as a therapeutic agent in NB. We show that VPF selectively and efficiently impairs the viability of YAP/TAZ-expressing NB GI-ME-N and SK-N-AS cells, but not of non-malignant fibroblasts. To investigate whether VPF-mediated NB cell killing is YAP-dependent, we tested VPF potency in CRISPR-mediated YAP/TAZ knock-out GI-ME-N cells, and BE(2)-M17 NB cells (a MYCN-amplified, predominantly YAP-negative NB subtype). Our data shows that VPF-mediated NB cell killing is not dependent on YAP expression. Moreover, we determined that the formation of higher molecular weight (HMW) complexes is an early and shared VPF-induced cytotoxic mechanism in both YAP-positive and YAP-negative NB models. The accumulation of HMW complexes, involving STAT3, GM130 and COX IV proteins, impaired cell homeostasis and triggered cell stress and cell death mechanisms. Altogether, our study shows significant in vitro and in vivo VPF-induced suppression of NB growth, making VPF a potential therapeutic candidate against NB.
    DOI:  https://doi.org/10.1038/s41598-023-29796-2
  17. Cells. 2023 Feb 24. pii: 717. [Epub ahead of print]12(5):
    RUNX3 Meets the Ubiquitin-Proteasome System in Cancer.
    Albano Toska, Nikita Modi, Lin-Feng Chen.
      RUNX3 is a transcription factor with regulatory roles in cell proliferation and development. While largely characterized as a tumor suppressor, RUNX3 can also be oncogenic in certain cancers. Many factors account for the tumor suppressor function of RUNX3, which is reflected by its ability to suppress cancer cell proliferation after expression-restoration, and its inactivation in cancer cells. Ubiquitination and proteasomal degradation represent a major mechanism for the inactivation of RUNX3 and the suppression of cancer cell proliferation. On the one hand, RUNX3 has been shown to facilitate the ubiquitination and proteasomal degradation of oncogenic proteins. On the other hand, RUNX3 can be inactivated through the ubiquitin-proteasome system. This review encapsulates two facets of RUNX3 in cancer: how RUNX3 suppresses cell proliferation by facilitating the ubiquitination and proteasomal degradation of oncogenic proteins, and how RUNX3 is degraded itself through interacting RNA-, protein-, and pathogen-mediated ubiquitination and proteasomal degradation.
    Keywords:  E3 ligase; RUNX3; proteasomal degradation; tumor suppressor; ubiquitination
    DOI:  https://doi.org/10.3390/cells12050717
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