mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma

Holmes, Brent; Benavides-Serrato, Angelica; Freeman, Ryan S.; Landon, Kenna A.; Bashir, Tariq; Nishimura, Robert N.; Gera, Joseph

doi:10.1038/onc.2017.360

Cited by 42 publications

(20 citation statements)

References 41 publications

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“…FAM3C up-regulates YY1 to induce HSF1 expression, finally activating Akt-Cyclin D1 pathway to promote the proliferation and migration of breast cancer cells. 47,48 TGFβ activated FAM3C-YY1-HSF1 axis to promote proliferation and migration in various breast cancer cell lines. Clearly, the roles of FAM3C, YY1 and HSF1 in the pathogenesis of breast cancer and/or other cancers should be considered as a whole.…”

Section: Discussionmentioning

confidence: 99%

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

Yang

Feng

Meng

et al. 2019

J Cellular Molecular Medi

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Family with sequence similarity three member C (FAM3C) (interleukin‐like EMT inducer [ILEI]), heat shock factor 1 (HSF1) and Ying‐Yang 1 (YY1) have been independently reported to be involved in the pathogenesis of various cancers. However, whether they are coordinated to trigger the development of cancer remains unknown. This study determined the role and mechanism of YY1 and HSF1 in FAM3C‐induced proliferation and migration of breast cancer cells. In human MDA‐MB‐231 breast cancer cell line, transforming growth factor‐β (TGFβ) up‐regulated FAM3C, HSF1 and YY1 expressions. FAM3C overexpression promoted the proliferation and migration of MDA‐MB‐231 cells with YY1 and HSF1 up‐regulation, whereas FAM3C silencing exerted the opposite effects. FAM3C inhibition repressed TGFβ‐induced HSF1 activation, and proliferation and migration of breast cancer cells. YY1 was shown to directly activate HSF1 transcription to promote the proliferation and migration of breast cancer cells. YY1 silencing blunted FAM3C‐ and TGFβ‐triggered activation of HSF1‐Akt‐Cyclin D1 pathway, and proliferation and migration of breast cancer cells. Inhibition of HSF1 blocked TGFβ‐, FAM3C‐ and YY1‐induced proliferation and migration of breast cancer cells. YY1 and HSF1 had little effect on FAM3C expression. Similarly, inhibition of HSF1 also blunted FAM3C‐ and TGFβ‐promoted proliferation and migration of human breast cancer BT‐549 cells. In human breast cancer tissues, FAM3C, YY1 and HSF1 protein expressions were increased. In conclusion, FAM3C activated YY1‐HSF1 signalling axis to promote the proliferation and migration of breast cancer cells. Furthermore, novel FAM3C‐YY1‐HSF1 pathway plays an important role in TGFβ‐triggered proliferation and migration of human breast cancer MDA‐MB‐231 cells.

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Section: Discussionmentioning

confidence: 99%

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

Yang

Feng

Meng

et al. 2019

J Cellular Molecular Medi

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“…The reduction of Hsp27 expression levels in the cells treated with resveratrol may be associated with downregulation of HSF1, the common transcription factor of Hsp. The modulation of HSF1 activation (trimerization and phosphorylation) by resveratrol is also likely to occur as a result of suppression of proteins which are involved in HSF activation such as MAPKs, AKT, or mTOR (Wang et al 2006;Banerjee Mustafi et al 2010;Dayalan Naidu et al 2016;Holmes et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol and siRNA in combination reduces Hsp27 expression and induces caspase-3 activity in human glioblastoma cells

Uçar

Şengelen

2019

Cell Stress and Chaperones

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GBM cells can easily gain resistance to conventional therapy, and therefore treatment of glioblastoma multiforme (GBM) is difficult. One of the hallmark proteins known to be responsible for this resistance is heat shock protein 27 (Hsp27) which has a key role in the cell survival. Resveratrol, a natural compound, exhibits antitumor effects against GBM, but there are no reports regarding its effect on Hsp27 expression in gliomas. The aim of the present study was to asses the effect of resveratrol on Hsp27 expression and apoptosis in non-transfected and transfected U-87 MG human glioblastoma cells. In order to block the Hsp27 expression, siRNA transfection was performed. Non-transfected and transfected cells were treated with either 10 or 15 μM resveratrol. The effects of resveratrol were compared with quercetin, a well-known Hsp27 inhibitor. Resveratrol was found to induce apoptosis more effectively than quercetin. Our data showed that resveratrol induces dose-and time-dependent cell death. We also determined that silencing of Hsp27 with siRNA makes the cells more vulnerable to apoptosis upon resveratrol treatment. The highest effect was observed in the 15 μM resveratrol and 25 nM siRNA combination group (suppressed Hsp27 expression by 93.4% and induced apoptosis by 101.2%). This study is the first report showing that resveratrol reduces Hsp27 levels, and siRNA-mediated Hsp27 silencing enhances the therapeutic effects of resveratrol in glioma cells. Our results suggest that resveratrol administration in combination with Hsp27 silencing has a potential to be used as a candidate for GBM treatment.

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“…HuR has been studied as an important driver and facilitator of cancer for almost 20 years and has been identified to be a critical target in numerous models of cancer. HuR has been found to regulate and contribute to almost every hallmark of cancer (Hanahan & Weinberg, 2011): (a) sustaining proliferative signaling (Holmes et al, 2018;W. Wang, Caldwell, Lin, Furneaux, & Gorospe, 2000;Yuan, Sanders, Ye, Wang, & Jiang, 2011;Z.…”

Section: Hur As Critical Mediator Of Cancer Progressionmentioning

confidence: 99%

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

et al. 2020

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Altered gene expression is a characteristic feature of many disease states such as tumorigenesis, and in most cancers, it facilitates cancer cell survival and adaptation. Alterations in global gene expression are strongly impacted by post‐transcriptional gene regulation. The RNA binding protein (RBP) HuR (ELAVL1) is an established regulator of post‐transcriptional gene regulation and is overexpressed in most human cancers. In many cancerous settings, HuR is not only overexpressed, but it is “overactive” as denoted by increased subcellular localization within the cytoplasm. This dysregulation of HuR expression and cytoplasmic localization allows HuR to stabilize and increase the translation of various prosurvival messenger RNA (mRNAs) involved in the pathogenesis of numerous cancers and various diseases. Based on almost 20 years of work, HuR is now recognized as a therapeutic target. Herein, we will review the role HuR plays in the pathophysiology of different diseases and ongoing therapeutic strategies to target HuR. We will focus on three ongoing‐targeted strategies: (1) inhibiting HuR's translocation from the nucleus to the cytoplasm; (2) inhibiting the ability of HuR to bind target RNA; and (3) silencing HuR expression levels. In an oncologic setting, HuR has been demonstrated to be critical for a cancer cell's ability to survive a variety of cancer relevant stressors (including drugs and elements of the tumor microenvironment) and targeting this protein has been shown to sensitize cancer cells further to insult. We strongly believe that targeting HuR could be a powerful therapeutic target to treat different diseases, particularly cancer, in the near future. This article is categorized under: RNA in Disease and Development > RNA in Disease NRA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Regulation

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mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma

Cited by 42 publications

References 41 publications

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

Resveratrol and siRNA in combination reduces Hsp27 expression and induces caspase-3 activity in human glioblastoma cells

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

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