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:10.1101/140293

Cited by 8 publications

(9 citation statements)

References 49 publications

(64 reference statements)

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“…FAM3C, family with sequence similarity three member C; YY1, Ying-Yang 1; HSF1, heat shock factor 1; TGFβ, transforming growth factor beta; Akt, protein kinase B role in activating Akt, it has also been reported that Akt activation also activates YY1 and HSF1 expressions. 47,48 TGFβ activated FAM3C-YY1-HSF1 axis to promote proliferation and migration in various breast cancer cell lines. Collectively, these findings together suggested that FAM3C likely initiates the crosstalks among YY1, HSF1 and Akt, finally causing excessive Akt activation to trigger tumour growth and invasion.…”

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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“…Previous studies showed that HuR promotes proliferation in cancer cells (20,38), including wild-type gliomas (39,40). Here, we investigated the effect of HuR expression on cell proliferation in cancer cells that harbor a natural heterozygous IDH1 mutation.…”

Section: Hur Promotes Cell Proliferation and Invasion In Mutidh1 Canmentioning

confidence: 98%

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer

Zarei

Lal

Vaziri‐Gohar

et al. 2019

Molecular Cancer Research

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Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of a-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant tumors is observed. In ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both isoforms were profoundly downregulated at the mRNA and protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites, nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy. Implications: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme.

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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, ): (a) sustaining proliferative signaling (Holmes et al, ; W. Wang, Caldwell, Lin, Furneaux, & Gorospe, ; Yuan, Sanders, Ye, Wang, & Jiang, ; Z. Zhang, Huang, Zhang, & Zhou, ); (b) evading suppression of growth (Balkhi et al, ; Ghosh et al, ); (c) promoting invasion and metastasis (Z. Li, Wang, Hu, Xu, & Xu, ); (d) enabling replicative immortality (Tang et al, ); (e) inducing angiogenesis (Goldberg‐Cohen, Furneauxb, & Levy, ; Levy et al, ; Osera et al, ); (f) resisting cell death (Blanco, Jimbo, et al, ; Guo et al, ; G. L. Lin et al, ; H. Zhu et al, ), (g) deregulating cellular energetics (Cascajo et al, ; Diaz‐Munoz et al, ; Zarei et al, ) (h) promoting tumor‐associated inflammation (W. Peng et al, ; S. Sun et al, ), and (i) avoiding immune destruction (Brauss et al, ). Further underscoring the importance of HuR as a target in cancer, increased levels of HuR have been associated with tumor aggressiveness and poor outcomes in numerous tumor types (Miyata et al, ).…”

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 8 publications

References 49 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

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer

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

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