bims-ectoca 2023-04-09 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–04–09
ten papers selected by
Ankita Daiya, Birla Institute of Technology and Science

FKBP11 improves the malignant property in osteosarcoma cells and acts as a prognostic factor of osteosarcoma.
The role and prospect of lysine-specific demethylases in cancer chemoresistance.
Exosomes and osteosarcoma drug resistance.
Esearch3D: propagating gene expression in chromatin networks to illuminate active enhancers.
Leveraging Advanced In Silico Techniques in Early Drug Discovery: A Study of Potent Small-Molecule YAP-TEAD PPI Disruptors.
A biomechanical view of epigenetic tumor regulation.
Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?
Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation.
The atypical ubiquitin ligase RNF31 stabilizes c-Myc via epigenetic inactivation of FBXO32 nd promotes cancer development.
Cytoplasmic YAP1-mediated ESCRT-III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer.

Aging (Albany NY). 2023 Apr 01. 15

FKBP11 improves the malignant property in osteosarcoma cells and acts as a prognostic factor of osteosarcoma.

Duo Zeng, Jiayu Li, Xuhui Yuan, Feng Cai, Bo Yu, Lang Liu, Qinchan Chen, FeiFei Zhang, Yiping Liang, Xiaofeng Tang, Yuanxiang Peng, Gaoyang Qu, Pengyun Wu, QuanHui Jiao, Longhua Sun, Xiao-Bin Lv, Qi Liao.

   BACKGROUND: Osteosarcoma has become the most common bone malignancy in adolescents. Although the clinical treatment of osteosarcoma has developed very much in recent years, the 5-year survival rate for patients with osteosarcoma has not improved significantly. Currently, many studies have shown that mRNA has a unique advantage as a target for drug therapy. Therefore, this study is dedicated to finding a new prognostic factor and providing a new target for the treatment of osteosarcoma to improve the prognosis of patients with osteosarcoma.
METHODS AND RESULTS: We selected the prognostic genes which are closely associated with osteosarcoma clinical features by obtaining osteosarcoma patients' information from the GTEx and TARGET database, then developed a risk model. We detected the expression of FKBP11 in osteosarcoma by qRT-PCR, Western blotting, and immunohistochemistry, and performed CCK8, transwell, colony formation, and flow cytometry to reveal the regulatory role of FKBP11. We found that FKBP11 was highly expressed in osteosarcoma, and silencing FKBP11 expression reduced the invasion and migration ability of osteosarcoma cells and slowed down cell proliferation, while promoting apoptosis. We also found that silencing the expression of FKBP11 led to inhibiting the phosphorylation of MEK/ERK.
CONCLUSIONS: In conclusion, we validated that the prognostic factor FKBP11 is closely associated with osteosarcoma and found a novel mechanism by which FKBP11 ameliorates the malignant properties of osteosarcoma cells through the MAPK pathway and serves as a prognostic factor in osteosarcoma. It provides a new idea for the treatment of osteosarcoma.

Keywords:  FKBP11; MAPK signaling pathway; osteosarcoma; prognosis

DOI:  https://doi.org/10.18632/aging.204523
Med Res Rev. 2023 Apr 03.

The role and prospect of lysine-specific demethylases in cancer chemoresistance.

Ying-Qi Song, Guan-Jun Yang, Dik-Lung Ma, Wanhe Wang, Chung-Hang Leung.

  Histone methylation plays a key function in modulating gene expression, and preserving genome integrity and epigenetic inheritance. However, aberrations of histone methylation are commonly observed in human diseases, especially cancer. Lysine methylation mediated by histone methyltransferases can be reversed by lysine demethylases (KDMs), which remove methyl marks from histone lysine residues. Currently, drug resistance is a main impediment for cancer therapy. KDMs have been found to mediate drug tolerance of many cancers via altering the metabolic profile of cancer cells, upregulating the ratio of cancer stem cells and drug-tolerant genes, and promoting the epithelial-mesenchymal transition and metastatic ability. Moreover, different cancers show distinct oncogenic addictions for KDMs. The abnormal activation or overexpression of KDMs can alter gene expression signatures to enhance cell survival and drug resistance in cancer cells. In this review, we describe the structural features and functions of KDMs, the KDMs preferences of different cancers, and the mechanisms of drug resistance resulting from KDMs. We then survey KDM inhibitors that have been used for combating drug resistance in cancer, and discuss the opportunities and challenges of KDMs as therapeutic targets for cancer drug resistance.

Keywords:  cancer; drug resistance; epigenetics; inhibitor; lysine-specific demethylases

DOI:  https://doi.org/10.1002/med.21955
Front Oncol. 2023 ;13 1133726

Exosomes and osteosarcoma drug resistance.

Huichao Fu, Yunjiao Wu, Jianbai Chen, Xing Hu, Xiaoyan Wang, Gongping Xu.

  Osteosarcoma (OS) is a primary malignant tumor of bone characterized by the formation of bone tissue or immature bone by tumor cells. Because of its multi-drug resistance, even with the improvement of chemotherapy and the use of targeted drugs, the survival rate of osteosarcoma (OS) is still less than 60%, and it is easy to metastasize, which is a difficulty for many clinicians and researchers. In recent years, with the continuous research on exosomes, it has been found that exosomes play a role in the diagnosis, treatment and chemotherapy resistance of osteosarcoma due to their unique properties. Exosomes can reduce the intracellular accumulation of chemotherapeutic drugs by mediating drug efflux, thus inducing chemotherapeutic resistance in OS cells. Exosomal goods (including miRNA and functional proteins) carried by exosomes also show great potential in affecting the drug resistance of OS. In addition, miRNA carried by exosomes and exosomes exist widely in tumor cells and can reflect the characteristics of parent cells, so it can also be used as a biomarker of OS. At the same time, the development of nanomedicine has given a new hope for the treatment of OS. Exosomes are regarded as good natural nano-carriers by researchers because of their excellent targeted transport capacity and low toxicity, which will play an important role in the field of OS therapy in the future. This paper reviews the internal relationship between exosomes and OS chemotherapy resistance, discusses the broad prospects of exosomes in the field of diagnosis and treatment of OS, and puts forward some suggestions for the study of the mechanism of OS chemotherapy resistance.

Keywords:  biomarkers; drug resistance; exosomes; osteosarcoma; treatment

DOI:  https://doi.org/10.3389/fonc.2023.1133726
Nucleic Acids Res. 2023 Apr 06. pii: gkad229. [Epub ahead of print]

Esearch3D: propagating gene expression in chromatin networks to illuminate active enhancers.

Maninder Heer, Luca Giudice, Claudia Mengoni, Rosalba Giugno, Daniel Rico.

Most cell type-specific genes are regulated by the interaction of enhancers with their promoters. The identification of enhancers is not trivial as enhancers are diverse in their characteristics and dynamic in their interaction partners. We present Esearch3D, a new method that exploits network theory approaches to identify active enhancers. Our work is based on the fact that enhancers act as a source of regulatory information to increase the rate of transcription of their target genes and that the flow of this information is mediated by the folding of chromatin in the three-dimensional (3D) nuclear space between the enhancer and the target gene promoter. Esearch3D reverse engineers this flow of information to calculate the likelihood of enhancer activity in intergenic regions by propagating the transcription levels of genes across 3D genome networks. Regions predicted to have high enhancer activity are shown to be enriched in annotations indicative of enhancer activity. These include: enhancer-associated histone marks, bidirectional CAGE-seq, STARR-seq, P300, RNA polymerase II and expression quantitative trait loci (eQTLs). Esearch3D leverages the relationship between chromatin architecture and transcription, allowing the prediction of active enhancers and an understanding of the complex underpinnings of regulatory networks. The method is available at: https://github.com/InfOmics/Esearch3D and https://doi.org/10.5281/zenodo.7737123.

DOI: https://doi.org/10.1093/nar/gkad229
J Chem Inf Model. 2023 Apr 03.

Leveraging Advanced In Silico Techniques in Early Drug Discovery: A Study of Potent Small-Molecule YAP-TEAD PPI Disruptors.

Ernest Awoonor-Williams, Callum J Dickson, Pascal Furet, Andrei A Golosov, Viktor Hornak.

Disruption of the YAP-TEAD protein-protein interaction is an attractive therapeutic strategy in oncology to suppress tumor progression and cancer metastasis. YAP binds to TEAD at a large flat binding interface (∼3500 Å2) devoid of a well-defined druggable pocket, so it has been difficult to design low-molecular-weight compounds to abrogate this protein-protein interaction directly. Recently, work by Furet and coworkers (ChemMedChem 2022, DOI: 10.1002/cmdc.202200303) reported the discovery of the first class of small molecules able to efficiently disrupt the transcriptional activity of TEAD by binding to a specific interaction site of the YAP-TEAD binding interface. Using high-throughput in silico docking, they identified a virtual screening hit from a hot spot derived from their previously rationally designed peptidic inhibitor. Structure-based drug design efforts led to the optimization of the hit compound into a potent lead candidate. Given advances in rapid high-throughput screening and rational approaches to peptidic ligand discovery for challenging targets, we analyzed the pharmacophore features involved in transferring from the peptidic to small-molecule inhibitor that could enable small-molecule discovery for such targets. Here, we show retrospectively that pharmacophore analysis augmented by solvation analysis of molecular dynamics trajectories can guide the designs, while binding free energy calculations provide greater insight into the binding conformation and energetics accompanying the association event. The computed binding free energy estimates agree well with experimental findings and offer useful insight into structural determinants that influence ligand binding to the TEAD interaction surface, even for such a shallow binding site. Taken together, our results demonstrates the utility of advanced in silico methods in structure-based design efforts for difficult-to-drug targets such as the YAP-TEAD transcription factor complex.

DOI: https://doi.org/10.1021/acs.jcim.3c00122
J Biol Phys. 2023 Apr 01.

A biomechanical view of epigenetic tumor regulation.

Boyuan Zhao, Yonggang Lv.

  The occurrence and development of tumors depend on a complex regulation by not only biochemical cues, but also biomechanical factors in tumor microenvironment. With the development of epigenetic theory, the regulation of biomechanical stimulation on tumor progress genetically is not enough to fully illustrate the mechanism of tumorigenesis. However, biomechanical regulation on tumor progress epigenetically is still in its infancy. Therefore, it is particularly important to integrate the existing relevant researches and develop the potential exploration. This work sorted out the existing researches on the regulation of tumor by biomechanical factors through epigenetic means, which contains summarizing the tumor epigenetic regulatory mode by biomechanical factors, exhibiting the influence of epigenetic regulation under mechanical stimulation, illustrating its existing applications, and prospecting the potential. This review aims to display the relevant knowledge through integrating the existing studies on epigenetic regulation in tumorigenesis under mechanical stimulation so as to provide theoretical basis and new ideas for potential follow-up research and clinical applications. Mechanical factors under physiological conditions stimulate the tumor progress through epigenetic ways, and new strategies are expected to be found with the development of epidrugs and related delivery systems.

Keywords:  Biomechanics; Epigenetics; Nucleus; Target therapy; Tumor

DOI:  https://doi.org/10.1007/s10867-023-09633-3
Front Genet. 2023 ;14 1148192

Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

Marco Corazzari, Licio Collavin.

  Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options.

Keywords:  ER stress; UPR; autophagy; ferroptosis; hypoxia; p53 tumor suppressor; stress response pathways; unfolded protein response

DOI:  https://doi.org/10.3389/fgene.2023.1148192
Haematologica. 2023 Apr 06.

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation.

Mengjia Li, Donghao Liu, Fumin Xue, Hengchao Zhang, Qianqian Yang, Lei Sun, Xiaoli Qu, Xiuyun Wu, Huizhi Zhao, Jing Liu, Qiaozhen Kang, Ting Wang, Xiuli An, Lixiang Chen.

Enhancer of zeste homolog 2 (EZH2) is the lysine methyltransferase of polycomb repressive complex 2 (PRC2) that catalyzes H3K27 tri-methylation. Aberrant expression and loss-of-function mutations of EZH2 have been demonstrated to be tightly associated with the pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as myelodysplastic syndrome (MDS). However, the function and mechanism of EZH2 in human erythropoiesis still remains largely unknown. Here, we demonstrated that EZH2 regulates human erythropoiesis in a stage-specific, dual-function manner by catalyzing histone and non-histone methylation. During the early erythropoiesis, EZH2 deficiency caused cell cycle arrest in the G1 phase, which impaired cell growth and differentiation. ChIP-seq and RNA-seq discovered that EZH2 knockdown caused a reduction of H3K27me3 and upregulation of cell cycle protein-dependent kinase inhibitors. In contrast, EZH2 deficiency led to the generation of abnormal nuclear cells and impaired enucleation during the terminal erythropoiesis. Interestingly, EZH2 deficiency downregulated the methylation of HSP70 by directly interacting with HSP70. RNA-seq analysis revealed that the expression of AURKB was significantly downregulated in response to EZH2 deficiency. Furthermore, treatment with an AURKB inhibitor and shRNA-mediated AURKB knockdown also led to nuclear malformation and decreased enucleation efficiency. These findings strongly suggest that EZH2 regulates terminal erythropoiesis through a HSP70 methylation-AURKB axis. Our findings have implications for improved understanding of ineffective erythropoiesis with EZH2 dysfunction.

DOI: https://doi.org/10.3324/haematol.2022.282016
Cell Signal. 2023 Apr 05. pii: S0898-6568(23)00091-8. [Epub ahead of print] 110677

The atypical ubiquitin ligase RNF31 stabilizes c-Myc via epigenetic inactivation of FBXO32 nd promotes cancer development.

Zefeng Chen, Dexu Ren, Jinyu Lv, Yuxin Xu, Mengru Xie, Xingbei He, Wen Shi, Qilan Qian, Aixin Jing, Xinhui Ma, Jingting Qin, Yuanyuan Ding, Ting Geng, Jinming Ma, Wei Liu, Shunfang Liu, Jing Ji.

  RNF31, an atypical E3 ubiquitin ligase of the RING-between-RING protein family, is one of the important components of the linear ubiquitin chain complex LUBAC. It plays a carcinogenic role in a variety of cancers by promoting cell proliferation, invasion and inhibiting apoptosis. However, the specific molecular mechanism by which RNF31 exerts its cancer-promoting effects is still unclear. By analyzing the expression profile of RNF31-depleted cancer cells, we found that loss of RNF31 significantly resulted in the inactivation of the c-Myc pathway. We further showed that RNF31 played an important role in the maintenance of c-Myc protein levels in cancer cells by extending the half-life of c-Myc protein and reducing its ubiquitination. c-Myc protein levels are tightly regulated by the ubiquitin proteasome, in which the E3 ligase FBXO32 is required to mediate its ubiquitin-dependent degradation. We found that RNF31 inhibited the transcription of FBXO32 through EZH2-mediated trimethylation of histone H3K27 in the FBXO32 promoter region, leading to the stabilization and activation of c-Myc protein. Under this circumstance, the expression of FBXO32 was significantly increased in RNF31-deficient cells, promoting the degradation of c-Myc protein, inhibiting cell proliferation and invasion, increasing cell apoptosis, and ultimately blocking the progression of tumors. Consistent with these results, the reduced malignancy phenotype caused by RNF31 deficiency could be partially reversed by overexpression of c-Myc or further knockdown of FBXO32. Together, our results reveal a key association between RNF31 and epigenetic inactivation of FBXO32 in cancer cells, and suggest that RNF31 may be a promising target for cancer therapy.

Keywords:  C-Myc; EZH2; Epigenetic; FBXO32; RNF31

DOI:  https://doi.org/10.1016/j.cellsig.2023.110677
Cancer Commun (Lond). 2023 Apr 02.

Cytoplasmic YAP1-mediated ESCRT-III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer.

Yan Guo, Yuqing Cui, Yangyang Li, Xiaoying Jin, Dandan Wang, Mengxia Lei, Fengzhi Chen, Yali Liu, Jinwen Xu, Guanyu Yao, Guangchun Zeng, Xuesong Chen.

   BACKGROUND: Nuclear Yes1-associated transcriptional regulator (YAP1) promotes tumor progression. However, the function of cytoplasmic YAP1 in breast cancer cells and its impact on the survival of breast cancer patients remain unclear. Our research aimed to explore the biological function of cytoplasmic YAP1 in breast cancer cells and the possibility of cytoplasmic YAP1 as a predictive marker of breast cancer survival.
METHODS: We constructed cell mutant models, including NLS-YAP15SA (nuclear localized), YAP1S94A (incapable of binding to the TEA domain transcription factor family) and YAP1S127D (cytoplasmic localized), and used Cell Counting Kit-8 (CCK-8) assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays, and Western blotting (WB) analysis to detect cell proliferation and apoptosis. The specific mechanism of cytoplasmic YAP1-mediated endosomal sorting complexes required for transport III (ESCRT-III) assembly was studied by co-immunoprecipitation, immunofluorescence staining, and WB analysis. Epigallocatechin gallate (EGCG) was used to simulate YAP1 retention in the cytoplasm in in vitro and in vivo experiments to study the function of cytoplasmic YAP1. YAP1 binding to NEDD4-like E3 ubiquitin protein ligase (NEDD4L) was identified using mass spectrometry and was verified in vitro. Breast tissue microarrays were used to analyze the relationship between cytoplasmic YAP1 expression and the survival of breast cancer patients.
RESULTS: YAP1 was mainly expressed in the cytoplasm in breast cancer cells. Cytoplasmic YAP1 promoted autophagic death of breast cancer cells. Cytoplasmic YAP1 bound to the ESCRT-III complex subunits charged multivesicular body protein 2B (CHMP2B) and vacuolar protein sorting 4 homolog B (VPS4B), promoting assembly of CHMP2B-VPS4B and activating autophagosome formation. EGCG retained YAP1 in the cytoplasm, promoting the assembly of CHMP2B-VPS4B to promote autophagic death of breast cancer cells. YAP1 bound to NEDD4L, and NEDD4L mediated ubiquitination and degradation of YAP1. Breast tissue microarrays revealed that high levels of cytoplasmic YAP1 were beneficial to the survival of breast cancer patients.
CONCLUSIONS: Cytoplasmic YAP1 mediated autophagic death of breast cancer cells by promoting assembly of the ESCRT-III complex; furthermore, we established a new breast cancer survival prediction model based on cytoplasmic YAP1 expression.

Keywords:  Autophagosome closure; Autophagy; Breast cancer; CHMP2B; Cytoplasmic YAP1; EGCG; ESCRT-III; Hippo pathway; NEDD4L; Ubiquitin; VPS4B

DOI:  https://doi.org/10.1002/cac2.12417