HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration

Abstract NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-β signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-β signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-β signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-β signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-β signaling related diseases.

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Abstract 17015: PGC-1alpha/Arhgap6 Axis Mediates Diabetic Vascular Dysfunction Through Diminution of Endothelial Glycolytic Flux

Circulation ◽

10.1161/circ.138.suppl_1.17015 ◽

2018 ◽

Vol 138 (Suppl_1) ◽

Author(s):

Makoto Ariyoshi ◽

Mariko Aoyagi-Keller ◽

Zolt Arany ◽

Naoki Sawada

Keyword(s):

Feedback Loop ◽

Therapeutic Potential ◽

Vascular Dysfunction ◽

Limb Ischemia ◽

High Rate ◽

Glycolytic Flux ◽

High Propensity ◽

And Migration ◽

Metabolic Module

Introduction: Aberrant angiogenesis in diabetes (DM) is caused by failure of local endothelial cells (ECs) to properly undergo VEGF-driven migration, and leads to a high propensity to develop critical limb ischemia. We recently showed that type 1 and 2 DM induce PGC-1α in ECs, which in turn strongly blocks EC migration and angiogenesis. Despite this therapeutic potential, PGC-1α may not be “druggable” due to the diverse distribution and functions in non-vascular tissues. Thus, understanding EC PGC-1α effectors is critical, which may involve bioenergetics since PGC-1α broadly induces mitochondrial OxPhos. Although ECs show high rate of glycolytic flux and synthesis of lactate, a burgeoning angiogenic mediator, this is blunted in DM via mechanisms still ill-defined. We hypothesized that a novel PGC-1α target in DM mediates blunted EC glycolysis and migration. Methods and Results: By leveraging NRF1/2-binding defective PGC-1α, we show that PGC-1α blocks glycolysis, through PPARgamma-driven Notch induction independent of mitochondrial activation, which fully accounts for PGC-1α inhibition of EC migration in DM. mRNA microarray identified ARHGAP6, a Rho-GAP and actin cytoskeletal modulator, as a DM-inducible main effector of PGC-1α axis to inhibit EC lactate synthesis and migration. Data suggest the causal role for ARHGAP6 in the reduced migration and glycolysis (Seahorse XF analyzer) of STZ-induced DM mouse ECs. Impaired migration of DM ECs and ECs overexpressing PPARgamma or ARHGAP6 was associated with decreased activity of Rac1 and rescued by addition of lactate. Reduced GTP-Rac1 in ECs overexpressing PGC-1α was restored by knockdown of ARHGAP6. Positive feedback loop between Rac1 and LDHA was demonstrated, suggesting a cytoskeletal-metabolic module to mediate EC migration and dysfunction. Conclusions: PGC-1α/ ARHGAP6 inhibition of EC glycolysis and lactate synthesis is a key mechanism of impaired EC migration in DM angiopathy. Our data provide important insights into the mechanistic link between EC actin cytoskeleton and bioenergetics mediated by ARHGAP6, and opportunities to restore diminished glycolysis in DM ECs by targeting PGC-1α axis component ARHGAP6 to develop safe and efficacious therapeutic since it is dispensable for health.

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A novel AP-1/miR-101 regulatory feedback loop and its implication in the migration and invasion of hepatoma cells

Nucleic Acids Research ◽

10.1093/nar/gku872 ◽

2014 ◽

Vol 42 (19) ◽

pp. 12041-12051 ◽

Cited By ~ 25

Author(s):

Jing-Jing Liu ◽

Xue-Jia Lin ◽

Xiao-Jing Yang ◽

Liangji Zhou ◽

Shuai He ◽

...

Keyword(s):

Feedback Loop ◽

Hepatoma Cells ◽

Migration And Invasion ◽

Regulatory Feedback Loop

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Mutant p53 amplifies a dynamin-1/APPL1 endosome feedback loop that regulates recycling and migration

The Journal of Cell Biology ◽

10.1083/jcb.201810183 ◽

2019 ◽

Vol 218 (6) ◽

pp. 1928-1942 ◽

Cited By ~ 8

Author(s):

Ashley M. Lakoduk ◽

Philippe Roudot ◽

Marcel Mettlen ◽

Heather M. Grossman ◽

Sandra L. Schmid ◽

...

Keyword(s):

Feedback Loop ◽

Migration And Invasion ◽

Mutant P53 ◽

Surface Receptors ◽

Protein Levels ◽

Early Endosomes ◽

Cell Progression ◽

Metastatic Activity ◽

Focal Adhesion Turnover ◽

And Migration

Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors downstream of gain-of-function (GOF) mutant p53. We report that dynamin-1 (Dyn1) is up-regulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Dyn1 is required for the recruitment and accumulation of the signaling scaffold, APPL1, to a spatially localized subpopulation of endosomes at the cell perimeter. We developed new tools to quantify peripherally localized early endosomes and measure the rapid recycling of integrins. We report that these perimeter APPL1 endosomes modulate Akt signaling and activate Dyn1 to create a positive feedback loop required for rapid recycling of EGFR and β1 integrins, increased focal adhesion turnover, and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus that integrates signaling and receptor trafficking, which can be co-opted and amplified in mutant p53–driven cancer cells to increase migration and invasion.

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Exosome-Transmitted miR-128 Targets CCL18 to Inhibit the Proliferation and Metastasis of Urothelial Carcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.760748 ◽

2022 ◽

Vol 8 ◽

Author(s):

Donghao Shang ◽

Yuting Liu ◽

Zhenghao Chen

Keyword(s):

Nude Mice ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Regulatory Function ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Normal Tissues ◽

T24 Cells ◽

Friendship Hospital ◽

And Migration

Objective: To investigate the regulatory function of exosome-transmitted miR-128 and chemokine (C-C motif) ligand 18 (CCL18) on urothelial carcinomas (UCs).Methods: Tumor tissues, paracancerous tissues, and serum were collected from 20 patients with UCs (diagnosed at Beijing Friendship Hospital, Capital Medical University). CCL18 was detected by immunohistochemistry and ELISA. PCR was used to measure the expression levels of CCL18 and mir-183, miR-128, mir-33a in UCs. We acquired exosomes from mesenchymal stem cells and synthesized exosomes overexpressing miR-128 (HMSC-128-EV). The effects of miR-128 on the migration and invasion abilities, apoptosis and epithelial-mesenchymal transition of BUC T24 cells were investigated by co-culturing HMSC-128-EV. The therapeutic potential of miR-128 on disease models was explored by injecting HMSC-128-EV into nude mice.Results: The expression of CCL18 in UCs was significantly higher than that in normal tissues (p < 0.05), and the serum level of CCL18 in patients with UC was significantly increased compared with those in healthy controls (p < 0.05). CCL18 overexpression or downregulation enhanced or suppressed the proliferation, migration and invasion of BUC T24 cells, resectively (p < 0.05). The exosome-transmitted miR-128 can inhibit cell proliferation (p < 0.05), invasion (p < 0.05), and migration (p < 0.05) in UCs, and these effects can be reversed by CCL18. In terms of apoptosis, miR-128 was able to promote the occurrence of BUC T24 apoptosis (p < 0.05), which can also be reversed by CCL18. In addition, miR-128 can inhibit the proliferation (p < 0.05) and metastasis (p < 0.05) of UCs in nude mice.Conclusion: The miR-128 inhibits the proliferation, invasion, migration of UCs, and promotes its apoptosis by regulating CCL18 secretion.

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HIF-3α-Induced miR-630 Expression Promotes Cancer Hallmarks in Cervical Cancer Cells by Forming a Positive Feedback Loop

10.21203/rs.3.rs-900566/v1 ◽

2021 ◽

Author(s):

Qiaohui Gao ◽

Zhenghua Ren ◽

Shengyuan Jiao ◽

Juan Guo ◽

Xia Miao ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Feedback Loop ◽

Migration And Invasion ◽

Rna Seq ◽

Cancer Hallmarks ◽

Potential Biomarker ◽

Cervical Cancer Cells ◽

Regulatory Feedback Loop ◽

Cervical Cancer Development

Abstract Background Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Methods We used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α or miR-630. ChIP-qPCR and RT-qPCR were used to validate the sequencing results of ChIP-seq and RNA-seq. Cellular, molecular and radiation experiments were used to explore the functions of miR-630.Results Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Conclusion Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.

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Eupatilin Inhibits the Proliferation and Migration of Prostate Cancer Cells through Modulation of PTEN and NF-κB Signaling

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200811113549 ◽

2020 ◽

Vol 20 ◽

Author(s):

Riza Serttas ◽

Cagla Koroglu ◽

Suat Erdogan

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Therapeutic Potential ◽

In Vivo Studies ◽

Migration And Invasion ◽

Prostate Cancer Cells ◽

And Migration ◽

Proliferation And Migration

Background: Despite advances in treatment of prostate cancer, side effects and the risks of developing drug resistance require new therapeutic agents. Eupatilin is a secondary metabolite of Artemisia asiatica and has shown potential anti-tumor activity in some cancers, but its potential in prostate cancer treatment has not yet been evaluated. Objective: The aim of the study was to investigate the effectiveness of eupatilin on prostate cancer cell proliferation and migration. Methods: Human prostate cancer PC3 and LNCaP cells were exposed to eupatilin and its efficacy on cell survival was determined by MTT test. Apoptosis and cell cycle phases were evaluated by image-based cytometer. Cell migration and invasion was evaluated by wound healing and matrigel migration assays; the expression of mRNA and protein were assessed by RT-qPCR and Western blot,respectively. Results: Eupatilin time- and dose-dependently reduced the viability of prostate cancer cells. Exposure of PC3 cells to 12.5 µM - 50 µM eupatilin resulted in apoptosis by upregulating the expression of caspase 3, Bax and cytochrome c. Annexin V assessment also confirmed that eupatilin causes apoptosis. The treatment significantly upregulated mRNA expression of p53, p21, and p27, causing cell cycle arrest in the G1 phase. Administration of eupatilin inhibited migration and invasion of the cells by down-regulating the expression of Twist, Slug and MMP-2, -7. In addition, the agent increased protein expression of tumor suppressor PTEN, while transcription factor NF-κB expression was reduced. Conclusion: Eupatilin strongly prevents proliferation of prostate cancer cells, and suppresses migration and invasion. Because of its therapeutic potential, the clinical use of eupatilin in prostate cancer should also be supported by in vivo studies.

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Novel players fine-tune plant trade-offs

Essays in Biochemistry ◽

10.1042/bse0580083 ◽

2015 ◽

Vol 58 ◽

pp. 83-100 ◽

Cited By ~ 25

Author(s):

Selena Gimenez-Ibanez ◽

Marta Boter ◽

Roberto Solano

Keyword(s):

Ubiquitin Ligase ◽

Feedback Loop ◽

Molecular Level ◽

26S Proteasome ◽

Signalling Molecules ◽

Transcriptional Reprogramming ◽

Trade Offs ◽

Jaz Proteins ◽

Regulatory Feedback Loop ◽

Fine Tune

Jasmonates (JAs) are essential signalling molecules that co-ordinate the plant response to biotic and abiotic challenges, as well as co-ordinating several developmental processes. Huge progress has been made over the last decade in understanding the components and mechanisms that govern JA perception and signalling. The bioactive form of the hormone, (+)-7-iso-jasmonyl-l-isoleucine (JA-Ile), is perceived by the COI1–JAZ co-receptor complex. JASMONATE ZIM DOMAIN (JAZ) proteins also act as direct repressors of transcriptional activators such as MYC2. In the emerging picture of JA-Ile perception and signalling, COI1 operates as an E3 ubiquitin ligase that upon binding of JA-Ile targets JAZ repressors for degradation by the 26S proteasome, thereby derepressing transcription factors such as MYC2, which in turn activate JA-Ile-dependent transcriptional reprogramming. It is noteworthy that MYCs and different spliced variants of the JAZ proteins are involved in a negative regulatory feedback loop, which suggests a model that rapidly turns the transcriptional JA-Ile responses on and off and thereby avoids a detrimental overactivation of the pathway. This chapter highlights the most recent advances in our understanding of JA-Ile signalling, focusing on the latest repertoire of new targets of JAZ proteins to control different sets of JA-Ile-mediated responses, novel mechanisms of negative regulation of JA-Ile signalling, and hormonal cross-talk at the molecular level that ultimately determines plant adaptability and survival.

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miR-375 inhibits the proliferation, migration and invasion of esophageal squamous cell carcinoma by targeting XPR1

Current Gene Therapy ◽

10.2174/1566523220666201229155833 ◽

2020 ◽

Vol 20 ◽

Author(s):

Wenbin Wu ◽

Yangmei Zhang ◽

Xiaowu Li ◽

Xiang Wang ◽

Yuan Yuan

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Luciferase Assay ◽

Migration And Invasion ◽

Promoting Effect ◽

Dual Luciferase Assay ◽

Invasion And Migration ◽

And Migration

Objective: The purpose of this study was to explore the mechanism of the miR-375/XPR1 axis in esophageal squamous cell carcinoma (ESCC) and provide a new idea for targeted therapy of ESCC. Methods: Differentially expressed genes in GEO and TCGA databases were analyzed by bioinformatics. The expression levels of miR-375 and XPR1 mRNA were detected by qRT-PCR. Protein expression of XPR1 was detected by western blot. Bioinformatics analysis and dual luciferase assay were conducted to confirm the targeting relationship between miR-375 and XPR1. The viability, proliferation, migration and invasion of cells in each treatment group were detected by CCK-8, colony formation, wound healing and Transwell assays. Results: Significantly down-regulated miR-375 and remarkably up-regulated XPR1 were observed in ESCC tissue and cells. Overexpression of miR-375 inhibited proliferation, invasion and migration of ESCC cells, and greatly reduced the promoting effect of XPR1 overexpression on cell proliferation, migration and invasion. Dual luciferase assay confirmed that miR-375 targeted and inhibited XPR1 expression in ESCC. Conclusion: These results demonstrate the regulatory role of the miR-375/XPR1 axis in ESCC cells and provide a new potential target for the precise treatment of patients with ESCC.

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Hispidulin inhibits proliferation, migration, and invasion by promoting autophagy via regulation of PPARγ activation in prostate cancer cells and xenograft models

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa108 ◽

2020 ◽

Author(s):

Yuanyuan Wang ◽

Shanqi Guo ◽

Yingjie Jia ◽

Xiaoyu Yu ◽

Ruiyu Mou ◽

...

Keyword(s):

Prostate Cancer ◽

Flavonoid Compound ◽

Migration And Invasion ◽

Prostate Cancer Cells ◽

Invasion And Migration ◽

Beneficial Effects ◽

Anticancer Properties ◽

Xenograft Models ◽

And Migration

ABSTRACT Prostate cancer (PCa) is one of the important factors of cancer deaths especially in the western countries. Hispidulin (4′,5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid compound proved to possess anticancer properties, but its effects on PCa are left to be released. The aims of this study were to investigate the effects and the relative mechanisms of Hispidulin on PCa development. Hispidulin administration inhibited proliferation, invasion, and migration, while accelerated apoptosis in Du145 and VCaP cells, which was accompanied by PPARγ activation and autophagy enhancement. The beneficial effects of Hispidulin could be diminished by PPARγ inhibition. Besides, Hispidulin administration suppressed PCa tumorigenicity in Xenograft models, indicating the anticancer properties in vivo. Therefore, our work revealed that the anticancer properties of Hispidulin might be conferred by its activation on PPARγ and autophagy.

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miR-29a sensitizes the response of glioma cells to temozolomide by modulating the P53/MDM2 feedback loop

Cellular & Molecular Biology Letters ◽

10.1186/s11658-021-00266-9 ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Qiudan Chen ◽

Weifeng Wang ◽

Shuying Chen ◽

Xiaotong Chen ◽

Yong Lin

Keyword(s):

Molecular Mechanism ◽

Feedback Loop ◽

Glioma Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Transcriptional Level ◽

Aberrant Expression ◽

Altered Expression ◽

P53 Signaling

AbstractRecently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future.

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