bims-ectoca 2022-09-04 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–09–04
twelve papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Cancer cell histone density links global histone acetylation, mitochondrial proteome and histone acetylase inhibitor sensitivity.
Hybrid Histone Deacetylase Inhibitor: an Effective Strategy for Cancer Therapy.
Sirtuin 6 protects against hepatic fibrogenesis by suppressing the YAP and TAZ function.
Methylation hallmarks on the histone tail as a linker of osmotic stress and gene transcription.
The role of LINC01419 in regulating the cell stemness in lung adenocarcinoma through recruiting EZH2 and regulating FBP1 expression.
SAR1A regulates the RhoA/YAP and autophagy signaling pathways to influence osteosarcoma invasion and metastasis.
Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing.
TRIM50 Inhibits Proliferation and Metastasis of Gastric Cancer via Promoting β-Catenin Degradation.
Can abnormal chromatin folding cause high-penetrance cancer predisposition?
The safety and efficiency of Photodynamic therapy for the treatment of osteosarcoma: a systematic review of in vitro experiment and animal model reports.
Down-Regulation of Ubiquitin-Specific Peptidase 9X Inhibited Proliferation, Migration and Invasion of Osteosarcoma via ERK1/2 and PI3K/Akt Signaling Pathways.
The Effect of Yes-Associated Protein on the Interaction Between the MEK/Extracellular Signal-Regulated Kinase and Hippo Pathways in Osteoblasts Co-Cultured With Fibroblast Growth Factor Receptor 2-Mutated Dura Cells.

Commun Biol. 2022 Aug 27. 5(1): 882

Cancer cell histone density links global histone acetylation, mitochondrial proteome and histone acetylase inhibitor sensitivity.

Christopher Bruhn, Giulia Bastianello, Marco Foiani.

Chromatin metabolism is frequently altered in cancer cells and facilitates cancer development. While cancer cells produce large amounts of histones, the protein component of chromatin packaging, during replication, the potential impact of histone density on cancer biology has not been studied systematically. Here, we show that altered histone density affects global histone acetylation, histone deactylase inhibitor sensitivity and altered mitochondrial proteome composition. We present estimates of nuclear histone densities in 373 cancer cell lines, based on Cancer Cell Line Encyclopedia data, and we show that a known histone regulator, HMGB1, is linked to histone density aberrations in many cancer cell lines. We further identify an E3 ubiquitin ligase interactor, DCAF6, and a mitochondrial respiratory chain assembly factor, CHCHD4, as histone modulators. As systematic characterization of histone density aberrations in cancer cell lines, this study provides approaches and resources to investigate the impact of histone density on cancer biology.

DOI: https://doi.org/10.1038/s42003-022-03846-3
Curr Med Chem. 2022 Aug 26.

Hybrid Histone Deacetylase Inhibitor: an Effective Strategy for Cancer Therapy.

Jiyong Wu, Jing Nie, Yepeng Luan, Yanjiao Ding.

  Inhibition of histone deacetylases (HDACs) has proven to be an effective strategy for cancer therapy. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It is proposed an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in both preventing resistance to treatment and potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDACi. Representative classes of reported hybrid HDACis are reviewed here with the purpose of shedding light on the design of novel hybrid HDACis for cancer therapy.

Keywords:  antitumor; bifunctional agent.; cancer therapy; histone deacetylase; hybrid; multitarget inhibitors

DOI:  https://doi.org/10.2174/0929867329666220826163626
FASEB J. 2022 10;36(10): e22529

Sirtuin 6 protects against hepatic fibrogenesis by suppressing the YAP and TAZ function.

Kushan Chowdhury, Menghao Huang, Hyeong-Geug Kim, X Charlie Dong.

  Hepatic fibrosis occurs in response to prolonged tissue injury in the liver, which results in abnormal accumulation of extracellular matrix. Hepatic stellate cells (HSCs) have been suggested to play a major role in liver fibrosis. However, the molecular mechanisms remain incompletely understood. Sirtuin 6 (SIRT6), an NAD+ -dependent deacetylase, has been previously implicated in the regulation of the transforming growth factor β (TGFβ)-SMAD3 pathway that plays a significant role in liver fibrosis. In this work, we aimed to identify other important players during hepatic fibrogenesis, which are modulated by SIRT6. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ or WWTR1), key players in the Hippo pathway, have been implicated in the promotion of hepatic fibrosis. Our data show that HSC-specific Sirt6 knockout mice are more susceptible to high-fat-cholesterol-cholate diet-induced hepatic fibrosis than their wildtype counterparts. Our signaling analyses suggest that in addition to the TGFβ-SMAD3 pathway, YAP and TAZ are also highly activated in the SIRT6-deficient HSCs. As it is not clear how SIRT6 might regulate YAP and TAZ, we have decided to elucidate the mechanism underlying the regulation of YAP and TAZ by SIRT6 in HSCs. Overexpression or knockdown of SIRT6 corroborates the role of SIRT6 in the negative regulation of YAP and TAZ. Further biochemical analyses reveal that SIRT6 deacetylates YAP and TAZ and reprograms the composition of the TEA domain transcription factor complex to suppress their downstream target genes, particularly those involved in hepatic fibrosis. In conclusion, our data suggest that SIRT6 plays a critical role in the regulation of the Hippo pathway to protect against hepatic fibrosis.

Keywords:  Sirtuin 6; TEAD; deacetylation; fibrosis; hippo

DOI:  https://doi.org/10.1096/fj.202200522R
Front Plant Sci. 2022 ;13 967607

Methylation hallmarks on the histone tail as a linker of osmotic stress and gene transcription.

Mu Xiao, Jinbiao Wang, Fang Xu.

  Plants dynamically manipulate their gene expression in acclimation to the challenging environment. Hereinto, the histone methylation tunes the gene transcription via modulation of the chromatin accessibility to transcription machinery. Osmotic stress, which is caused by water deprivation or high concentration of ions, can trigger remarkable changes in histone methylation landscape and genome-wide reprogramming of transcription. However, the dynamic regulation of genes, especially how stress-inducible genes are timely epi-regulated by histone methylation remains largely unclear. In this review, recent findings on the interaction between histone (de)methylation and osmotic stress were summarized, with emphasis on the effects on histone methylation profiles imposed by stress and how histone methylation works to optimize the performance of plants under stress.

Keywords:  gene transcription; histone demethylation; histone methylation; osmotic stress; stress memory

DOI:  https://doi.org/10.3389/fpls.2022.967607
Biol Direct. 2022 Sep 01. 17(1): 23

The role of LINC01419 in regulating the cell stemness in lung adenocarcinoma through recruiting EZH2 and regulating FBP1 expression.

Zhao Chen, Weijian Tang, Yuhan Zhou, Zhengfu He.

   BACKGROUND: Recent years have witnessed a growing academic interest in the effects of lncRNAs on tumors. LINC01419 is found to facilitate proliferation and metastasis of lung adenocarcinoma (LUAD) cells, but there is a great deal of uncertainty about how LINC01419 works on LUAD cell stemness. For this reason, the focus of this research is centered on the regulatory impact of LINC01419 on LUAD cell stemness.
METHODS: For the detection of the expression level of LINC01419 in LUAD, qRT-PCR was performed. And how oe-LINC01419 and sh-LINC01419 affected LUAD cell proliferation as well as stem cell sphere-formation were examined by CCK-8 and cell sphere-forming assays. In addition, whether LINC01419 could recruit EZH2 and regulate FBP1 expression were determined by bioinformatics analysis, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP). Western blot was utilized to detect the protein expression levels of FBP1, CD44, CD133, and ALDH-1 as well.
RESULTS: On the basis of the findings from those assays, an up-regulation of LINC01419 level was demonstrated in LUAD cell lines, and a remarkable upregulation of it in CD44 + LUAD cells. In LUAD cells, proliferation and stem cell sphere-formation that were attenuated by LINC01419 knockdown were discovered to be facilitated by LINC01419 overexpression. And a binding relationship between LINC01419 and EZH2 was determined by RIP assay. Besides, EZH2 was capable of binding to FBP1 promoter region, as found by ChIP-PCR assay. Finally, it was demonstrated by in vitro experiments that LINC01419 could inhibit FBP1 expression by recruiting EZH2, resulting in promotion of LUAD cell proliferation and stemness.
SIGNIFICANCE: To summarize, our findings demonstrate a cancer-promoting role of LINC01419 in LUAD. LINC01419, by recruiting EZH2 and regulating FBP1 expression, contributes to LUAD cell stemness. According to these findings, the potential of LINC01419 to be the target for LUAD treatment is hence determined, which also adds more possibility to the enrichment of therapeutic strategies for lung cancer stem cells.

Keywords:  Cancer stem cell; EZH2; FBP1; LINC01419; Lung adenocarcinoma

DOI:  https://doi.org/10.1186/s13062-022-00336-8
Cancer Sci. 2022 Sep 01.

SAR1A regulates the RhoA/YAP and autophagy signaling pathways to influence osteosarcoma invasion and metastasis.

Fangbiao Zhan, Qianrong Deng, Zhiyu Chen, Chaozheng Xie, Shuang Xiang, Sheng Qiu, Lin Tian, Chunrong Wu, Yunsheng Ou, Jian Chen, Lixin Xu.

  Osteosarcoma is the most prevalent form of primary bone malignancy affecting adolescents. SAR1A is a key regulator of endoplasmic reticulum (ER) homeostasis, but its role as a regulator of osteosarcoma metastasis has yet to be clarified. Bioinformatics analyses revealed SAR1A and RHOA to be upregulated in osteosarcoma patients, with the upregulation of these genes being associated with poor 5-year metastasis-free survival rates. In addition, the upregulation of SAR1A and RHOA in osteosarcoma was highly positively correlated. Immunohistochemical analyses additionally revealed that SAR1A levels were increased in osteosarcoma pulmonary metastases. In vitro wound healing and Transwell assays indicated that knocking down SAR1A or RHOA impaired the invasive and migratory activity of osteosarcoma cells, whereas RHOA overexpression had the opposite effect. Western blotting and immunofluorescent staining revealed the inhibition of osteosarcoma cell epithelial-mesenchymal transition following SAR1A or RHOA knockdown, RHOA overexpression had the opposite effect. Following SAR1A knockdown, phalloidin staining indicated that osteosarcoma cells exhibited reduced lamellipodia formation. ER stress levels and reactive oxygen species (ROS) production were enhanced following the knockdown of SAR1A, as was autophagic activity, with lung metastases being reduced in vivo after such knockdown. Knocking down SAR1A suppresses osteosarcoma cell metastasis via the RhoA/YAP, ER stress, and autophagic pathways, offering new insights into the regulation of autophagic activity in the context of osteosarcoma cell metastasis and suggesting that these pathways may be amenable to therapeutic intervention.

Keywords:  ER stress; RhoA/YAP; SAR1A; autophagy; metastasis

DOI:  https://doi.org/10.1111/cas.15551
Clin Epigenetics. 2022 Aug 27. 14(1): 107

Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing.

Yohannis Wondwosen Ahmed, Berhan Ababaw Alemu, Sisay Addisu Bekele, Solomon Tebeje Gizaw, Muluken Fekadie Zerihun, Endriyas Kelta Wabalo, Maria Degef Teklemariam, Tsehayneh Kelemu Mihrete, Endris Yibru Hanurry, Tensae Gebru Amogne, Assaye Desalegne Gebrehiwot, Tamirat Nida Berga, Ebsitu Abate Haile, Dessiet Oma Edo, Bizuwork Derebew Alemu.

  Nanopore sequencing has brought the technology to the next generation in the science of sequencing. This is achieved through research advancing on: pore efficiency, creating mechanisms to control DNA translocation, enhancing signal-to-noise ratio, and expanding to long-read ranges. Heterogeneity regarding epigenetics would be broad as mutations in the epigenome are sensitive to cause new challenges in cancer research. Epigenetic enzymes which catalyze DNA methylation and histone modification are dysregulated in cancer cells and cause numerous heterogeneous clones to evolve. Detection of this heterogeneity in these clones plays an indispensable role in the treatment of various cancer types. With single-cell profiling, the nanopore sequencing technology could provide a simple sequence at long reads and is expected to be used soon at the bedside or doctor's office. Here, we review the advancements of nanopore sequencing and its use in the detection of epigenetic heterogeneity in cancer.

Keywords:  CpG island; Epigenetics; Methylated cytosine; MinION; Nanopore sequencing; Oxford nanopore; Tumor heterogeneity

DOI:  https://doi.org/10.1186/s13148-022-01323-6
J Oncol. 2022 ;2022 5936753

TRIM50 Inhibits Proliferation and Metastasis of Gastric Cancer via Promoting β-Catenin Degradation.

Rongzhou Li, Peng Xu, Xiaosheng Jin, Zhengchao Shi, Qingqing Zhang, Fangpeng Ye, Weilai Yu, Tingting Ji.

Background: Gastric cancer (GC) is a common malignancy with a poor prognosis. Tripartite motif-containing 50 (TRIM50) belongs to the TRIM family and is reported to be related to numerous cancers. This study aimed to investigate the function of TRIM50 in GC.
Methods: Three microarray datasets (GSE13911, GSE79973, and GSE19826) containing GC and adjacent nontumor tissues were used for bioinformatics analysis to screen GC-related genes and assess the associations between GC development and TRIM50 expression. Then, TRIM50 expression in GC cells was detected at mRNA and protein levels. After TRIM50 was knockdown or overexpressed, the effect of TRIM50 on the proliferation and metastasis of GC cells was analyzed using Cell Counting Kit-8 (CCK-8), flow cytometry, scratch, and Transwell assays. The interaction between TRIM50 and β-catenin was analyzed. The expression of cell cycle-, migration-, invasion-, and Wnt/β-catenin signaling pathway-related proteins was detected by Western blot. Furthermore, we measured the role of TRIM50 overexpression on tumor growth as well as the Wnt/β-catenin signaling pathway in vivo. In addition, XAV939 (a WNT/β-catenin signaling pathway inhibitor) was used to clarify the mechanism of TRIM50 on GC.
Results: Bioinformatics revealed that TRIM50 expression was decreased in GC samples and associated with GC development. In vitro study revealed that TRIM50 overexpression impeded the GC cell proliferation and metastasis, while TRIM50 knockdown presented the opposite results. In addition, TRIM50 interacted with β-catenin to induce the degradation of β-catenin. In in vivo assay, TRIM50 overexpression inhibited tumor growth and blocked the Wnt/β-catenin signaling pathway. In addition, TRIM50 knockdown-promoted cell proliferation and metastasis in GC cells were inverted by XAV939.
Conclusion: TRIM50 overexpression may inhibit cell proliferation and metastasis in GC via β-catenin degradation, indicating that TRIM50 could be a target for the treatment of GC.

DOI: https://doi.org/10.1155/2022/5936753
Physiol Genomics. 2022 Aug 29.

Can abnormal chromatin folding cause high-penetrance cancer predisposition?

Mathias Schwartz.

Sequencing cancer predisposing genes (CPG) in evocative patients (i.e. patients with personal and family history of multiple/early-onset/unusual cancers) allows to adapt follow-up in their relatives when a causative pathogenic variant is identified. Unfortunately, many evocative families remain unexplained. Part of this "missing heritability" could be due to CPG dysregulations caused by remote non-coding genomic alterations. Transcription levels are regulated through the ability of promoters to physically interact with their distant cis-regulatory elements. Three-dimensional chromatin contacts, mediated by a dynamic loop extrusion process, are uncovered by chromosome conformation capture (3C) and 3C-derived techniques, which have enabled the discovery of new pathological mechanisms in developmental diseases and cancers. High-penetrance cancer predisposition are caused by germline hereditary alterations otherwise found at somatic level in sporadic cancers. Thus, data from both developmental diseases and cancers provide information about possible unknown cancer predisposition mechanisms. This minireview aims to deduce from these data whether abnormal chromatin folding can cause high-penetrance cancer predisposition.

DOI: https://doi.org/10.1152/physiolgenomics.00052.2022
Photodiagnosis Photodyn Ther. 2022 Aug 25. pii: S1572-1000(22)00379-9. [Epub ahead of print] 103093

The safety and efficiency of Photodynamic therapy for the treatment of osteosarcoma: a systematic review of in vitro experiment and animal model reports.

Gang Tan, Jing Xu, Qin Yu, Zeyu Yang, Hui Zhang.

   BACKGROUND: Osteosarcoma (OS) is an aggressive malignant bone tumour with high mortality. A poor prognosis is noted in patients with distal metastases or multidrug resistance. As an emerging antitumor strategy, photodynamic therapy (PDT) mediated by visible and near infrared light has attracted intensive attention given its target selectivity, remote controllability, minimal or non-invasive features . However, PDT also has obvious limitations. Specifically, due to the limited penetration of light, it is mainly used in the clinical treatment of superficial malignant tumours, such as musculoskeletal sarcomas and melanoma, but it has not been applied to the clinical treatment of deep malignant bone tumours except for a very small number of experiments on deep canine OS models.
MATERIALS AND METHODS: We searched for studies that focused on the effectiveness and safety of PDT for OS based on in vitro experiments and animal models in the last decade. A systematic search was conducted using electronic databases, including PubMed, ClinicalTrials.gov, and the Cochrane Library.
INCLUSION CRITERIA: (1) original research articles about PDT for OS; (2) articles in English; (3) in vitro or animal model research; and (4) detailed information, including cell name, fluence, irradiation wavelength, time of incubation with PS, duration between PS treatment and irradiation, and duration between irradiation and viability assays.
EXCLUSION CRITERIA: (1) study was a review/systemic review article, patent, letter, or conference abstract/paper; (2) articles were not published in English; (3) studies containing overlapping or insufficient data.
RESULTS: We identified 201 publications, and 44 articles met the inclusion criteria and were included in the synthesis. Unfortunately, there are no relevant clinical reports of the use of PDT in the treatment of human OS. In these studies, 8 studies only employed in vivo experiments to evaluate the efficiency of PDT in an OS animal model, 19 studies exclusively performed in vitro viability assays of cells treated with PDT under different conditions, and 17 studies included in vitro cell experiments and in vivo animal OS models to evaluate the effect of PDT on OS in vivo and in vitro. All studies have shown that PDT is cytotoxic to OS cells or can inhibit the growth of OS in heterologous or homologous animal OS models but exhibits minimal cytotoxicity at a certain range of dosages.
CONCLUSION: Based on this systematic review, PDT can eradicate OS cells in cell culture and there is some evidence for efficacy in animal models. However, the ability for PDT to control human OS is unclear, the animal and human reports do not show evidence of human OS control, they just do show feasibility. The major issues concerning the potential for treatment of osteosarcoma with PDT are that adequate light should be transmitted to tumor loci and if the disease is caught before metastasis and irradiation of tumor sites is feasible, curative potential is there. Otherwise, PDT may be mainly palliative. To determine whether PDT can safely and efficiently be used in the clinical treatment of OS, many preclinical orthotopic animal OS models and OS models of multiple systemic metastases must be performed and interstitial PDT or intraoperative PDT may be a good and potential candidate for human OS treatment. If these problems can be well solved, PDT may be a potentially effective strategy for the treatment of OS patients.

Keywords:  animal model; in vitro experiment; osteosarcoma; photodynamic therapy

DOI:  https://doi.org/10.1016/j.pdpdt.2022.103093
Biol Pharm Bull. 2022 ;45(9): 1283-1290

Down-Regulation of Ubiquitin-Specific Peptidase 9X Inhibited Proliferation, Migration and Invasion of Osteosarcoma via ERK1/2 and PI3K/Akt Signaling Pathways.

Wendi Zheng, Shuang Li, Jincheng Huang, Yonghui Dong, Hongjun Zhang, Jia Zheng.

  Ubiquitin-specific peptidase 9X (USP9X) has been reported to be closely associated with the formation and progression of a variety of malignant tumors. However, the mechanism by which USP9X is involved in osteosarcoma and development has not been clearly studied. This work aimed to probe the influence of USP9X on osteosarcoma cell proliferation, migration and invasion. This study recruited sixty-seven patients with histologically definited osteosarcoma. Osteosarcoma samples and cell-line were used to reflect the expression level of USP9X. Analysis of cell proliferation by thiazolium blue (MTT) assays. Transwell experiments and wound healing were used to verify cell migration and invasion capabilities. The effect of USP9X was investigated through in vivo experiments. USP9X-related pathway proteins were detected by Western blot and quantitative real-time PCR (qRT-PCR). The expression of USP9X in osteosarcoma was higher than that in adjacent tissues. The overall survival of patients with USP9X-negative patients was better than that of patients with USP9X-positive. The growth of osteosarcoma cells in vivo and in vitro was inhibited by USP9X inhibitor. Cell migration and invasion were significantly inhibited by down-regulation of USP9X. USP9X was involved in extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinases/protein-serine-threonine kinase (PI3K/Akt) pathway in osteosarcoma cells. Proliferation, migration and invasion of osteosarcoma cells were inhibited by down-regulation of USP9X, and were related to the ERK1/2 and PI3K/Akt signaling pathways, therefore, it might probably become a new target for the prevention and treatment of osteosarcoma.

Keywords:  invasion; migration; osteosarcoma; proliferation; ubiquitin-specific peptidase 9X

DOI:  https://doi.org/10.1248/bpb.b22-00198
J Craniofac Surg. 2022 Jun 01. 33(4): 1250-1254

The Effect of Yes-Associated Protein on the Interaction Between the MEK/Extracellular Signal-Regulated Kinase and Hippo Pathways in Osteoblasts Co-Cultured With Fibroblast Growth Factor Receptor 2-Mutated Dura Cells.

Xinhang Dong, Mingzi Zhang, Chengcheng Li, Chenzhi Lai, Guodong Song, Xiaolei Jin.

BACKGROUND: C342Y (Cys342Tyr) point mutation of FGFR2 (fibroblast growth factor receptor 2) is closely associated with the pathogenesis of Crouzon syndrome. The dura mater plays an important role in mediating the closure of cranial sutures. However, the underlying mechanisms of these pathological processes have been rarely investigated. in this study, the authors analyzed the effects of dura cells with FGFR2 mutations on the biological function of osteoblasts.
METHODS: Dura cells and cranial osteoblasts from C57BL/6 mice were extracted and cultured. C342Y-FGFR2 mutant constructs were established via lentivirus and applied to infect dura cells. A co-cultured trans-well system with dura cells and osteoblasts was established. Three experimental groups were set up: oste group, Oste + Dura-vector group, and Oste + Dura-C342Y group. The expression levels of key factors in MEK (Mitogen-activated protein kinase kinase, MAPKK)/extracellular signal-regulated kinase (ERK) and Hippo pathway were detected by western blot and RT-qPCR (Real Time Quantitative PCR). Finally, a rescue experiment was carried out with small interference RUA.
RESULTS: The proliferation level of osteoblasts in Oste + Dura- C342Y group was significantly up-regulated. Our studies indicated that the activation of MEK/ERK pathway in Oste + Dura-C342Y group could inhibit the Hippo pathway, lead to down-regulation of large tumor suppressor 1 and promote the activation and nuclear localization of yes-associated protein, and the results of rescue experiments showed a reverse expression trend, further confirming the effects of C342Y-FGFR2 mutation in dura cells on osteoblasts and its potential mechanism.
CONCLUSIONS: This study suggested that the C342Y-FGFR2 mutation in dura cells could promote osteoblastic proliferation, and shown the crosstalk between MEK/ERK and Hippo pathways. As the regulatory machinery center, yes-associated protein might play a bridging role in these pathways, and might influence the pathogenesis of craniosynostosis by activating downstream transcriptional factors.

DOI: https://doi.org/10.1097/SCS.0000000000008115