A p53-Responsive miRNA Network Promotes Cancer Cell Quiescence

La, Ting; Liu, Guang Zhi; Farrelly, Margaret; Cole, Nicole; Feng, Yu Chen; Sherwin, Simonne; Yari, Hamed; Tabatabaee, Hessam; Yan, Xu Guang; Guo, Su; Liu, Tao; Thorne, Rick F.; Jin, Lei; Zhang, Xu Dong

doi:10.1158/0008-5472.can-18-1886

Cited by 32 publications

(23 citation statements)

References 41 publications

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“…5h, i) we hypothesized that SWI/SNF (SMARCA2, SMARCB1, and ARID1A) mutations may deactivate the GR axis. In addition, we hypothesise that TP53 can also contribute to inactivation of GR signalling, as it is a well-established crucial regulator of quiescence 33,34 and crosstalk with GR was previously proposed 35 .…”

Section: Cdkn1c Foxo1 and Irs2 Form A Tumour Suppressor Axis In Hummentioning

confidence: 73%

Glucocorticoids regulate cancer cell dormancy

Prekovic

Schuurman

Manjón

et al. 2019

Preprint

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The glucocorticoid receptor directly regulates thousands of genes across the human genome in a cell-type specific manner, governing various aspects of homeostasis. The influence of the glucocorticoid receptor is also seen in various pathologies, including cancer, where it has been linked to tumorigenesis, metastasis, apoptosis resistance, and therapy bypass. Nonetheless, the direct genetic and molecular underpinnings of glucocorticoid action in cancer remain elusive. Here, we dissected the glucocorticoid receptor signalling axis and uncovered the mechanism of glucocorticoid-mediated cancer cell dormancy. Upon glucocorticoid receptor activation cancer cells undergo quiescence, subserved by cell cycle arrest through CDKN1C and reprogramming of signalling orchestrated via FOXO1/IRS2. Strikingly, co-expression of these three genes, directly regulated by glucocorticoid-induced chromatin looping, correlates with a benign molecular phenotype across human cancers, whereas triple loss is associated with increased expression of proliferation/aggressiveness markers. Finally, we show that the glucocorticoid receptor signalling axis is inactivated by alterations of either the chromatin remodelling complex or TP53 in vitro and in vivo. Our results indicate that the activation of the glucocorticoid receptor leads to cancer cell dormancy, which has several implications in terms of glucocorticoid use in cancer therapy. MainThe Glucocorticoid Receptor (GR) is a member of the nuclear hormone receptor superfamily and a ligand-activated transcription factor 1 . This multidomain protein exerts its function through chromatin binding and communication with the transcriptional machinery, ultimately modulating expression of several hundreds of genes, ubiquitously across diverse cell types 2 . As a homeostatic regulator, GR has an imperative role in neuroendocrine integration, circadian rhythm, immune system control, and glucose metabolism 3 . GR action extends beyond general physiology as its impact can be seen in various disease types, including cancer where it has been linked to tumorigenesis 4 , metastasis 5 , apoptosis resistance 6 , and therapy bypass 7 .As demonstrated using aged mouse haploinsufficiency models, GR loss predisposes to tumour development across multiple organ systems 4 . These findings are further substantiated by studies linking glucocorticoids (GCs) to growth-arrest in cell culture based tumour models 8,9 . Despite the reported influence on tumour biology, the direct genetic and molecular underpinnings of GC-action remain elusive.Herein, we examine the mechanism of GC-regulated cancer cell dormancy, using a multidisciplinary approach to dissect the GR axis and illustrate pathophysiological relevance thereof in human tumours. We show that GR activation leads to acquisition of quiescence, subserved by cell cycle arrest through CDKN1C and reprogramming of signalling orchestrated via FOXO1/IRS2. Strikingly, co-expression of these three genes, directly regulated by GC-induced chromatin looping, correlates with a benign...

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Section: Cdkn1c Foxo1 and Irs2 Form A Tumour Suppressor Axis In Hummentioning

confidence: 73%

Glucocorticoids regulate cancer cell dormancy

Prekovic

Schuurman

Manjón

et al. 2019

Preprint

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“…Cells were cultured in a humidified incubator at 37°C and 5% CO 2 and were tested using RT-PCR for mycoplasma contamination. Individual cell line authentication was confirmed using the AmpFISTR Identifiler PCR Amplification Kit from Applied Biosystems and GeneMarker V1.91 software (SoftGenetics LLC) 63 .…”

Section: Methodsmentioning

confidence: 99%

c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

et al. 2020

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The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.

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“…Intestinal gastric cancer cells suppress COL1A2 via miR-25 to promote EMT and angiogenesis [95]. MiR-27b-3p and miR-455-3p enhance cancer cell quiescence in response to activated p53 to increase drug resistance and recurrence [96]. The miRNA let-7d inhibits pancreatic stellate cell activation [97] and macrophage infiltration by targeting COL3A1 in renal cell carcinoma [98].…”

Section: The Relationship Among Exosomes Micrornas and Collagen In Cmentioning

confidence: 99%

The role of collagen in cancer: from bench to bedside

et al. 2019

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Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.

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A p53-Responsive miRNA Network Promotes Cancer Cell Quiescence

Cited by 32 publications

References 41 publications

Glucocorticoids regulate cancer cell dormancy

Glucocorticoids regulate cancer cell dormancy

c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

The role of collagen in cancer: from bench to bedside

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