Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells

Basu-Roy, Upal; Bayın, N. Sumru; Rattanakorn, Kirk; Han, Eugenia J.; Placantonakis, Dimitris G.; Mansukhani, Alka; Basilico, Claudio

doi:10.1038/ncomms7411

Cited by 223 publications

(229 citation statements)

References 67 publications

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“…Interestingly, upregulation of the stem cell transcription factor SOX2 antagonizes the Hippo pathway leading to exaggerated YAP function [48]. The upregulation of miR-181a and SOX2 transcripts that we observed in K562-STI-R cells, and the positive regulation of YAP in these cells, indicated a mechanistic relationship between these elements.…”

Section: Inhibition Of Mir-181a Does Not Significantly Affect Prolifementioning

confidence: 68%

Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

Chorzalska

Kim

Roder

et al. 2017

Stem Cells and Development

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Despite the success of tyrosine kinase inhibitor (TKI) therapy in chronic myelogenous leukemia (CML), leukemic stem/progenitor cells remain detectable even in the state of deep molecular remission. Mechanisms that allow them to persist despite continued kinase inhibition remain unclear. We have previously shown that prolonged exposure to imatinib mesylate (IM) results in dysregulation of Akt/Erk 1/2 signaling, upregulation of miR-181a, enhanced adhesiveness, and resistance to high IM. To characterize the molecular basis and reversibility of those effects, we applied gene and protein expression analysis, quantitative phosphoproteomics, and direct miR-181a inhibition to our cellular model of CML cells subjected to prolonged exposure to IM. Those cells demonstrated upregulation of pluripotency markers (SOX2, SALL4) and adhesion receptors (CD44, VLA-4, CXCR4), as well as downregulation of Hippo signaling and upregulation of transcription coactivator YAP. Furthermore, inhibition of miR-181a using a microRNA sponge inhibitor resulted in decreased transcription of SOX2 and SALL4, decreased activation of YAP, and increased sensitivity to IM. Our findings indicate that long-term exposure to IM results in dysregulation of stem cell renewal-regulatory Hippo/YAP signaling, acquisition of expression of stem cell markers and that experimental interference with YAP activity may help to restore chemosensitivity to TKI.

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Section: Inhibition Of Mir-181a Does Not Significantly Affect Prolifementioning

confidence: 68%

Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

Chorzalska

Kim

Roder

et al. 2017

Stem Cells and Development

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“…SOX2, a member of SRY-related HMG-box transcription factors families, is a well-established regulator of cell differentiation and development [27,28]. More than that, accumulating studies suggest that SOX2 acts as an oncogene in some cancers, such as skin squamous-cell carcinoma [29,30], lung squamouscell carcinoma [31,32], ovarian carcinoma [33], osteosarcomas [34] and glioblastoma [35].…”

Section: Discussionmentioning

confidence: 99%

miR-488 acts as a tumor suppressor gene in gastric cancer

Zhao

et al. 2016

Tumor Biol.

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Gastric cancer is one of the major causes of cancer mortality. Several microRNAs play a role in the tumor growth and invasion. However, the underlying molecular mechanism remains poorly understood. We detected the miR-638 expression levels in tumor samples and adjacent noncancerous tissues from 68 patients with gastric cancer as well as in the gastric cancer cell line SGC-7901 and SC-M1. The cell cycle was analyzed by flow cytometry, cell proliferation was observed by CCK-8 assay and cell invasion was detected using Transwell assay. MiR-638 was down-regulated in human GC tissues and its expression level was negatively correlated to TNM stage and lymph metastasis. In the cell lines, aberrant expression of miR-638 was related to the cell proliferation, cell cycle and invasion. We also found that SOX2 had a negative correlation with miR-638 in GC tissues, and miR-638 overexpression could decrease SOX2 expression level by directly binding the 3'-UTR of SOX2. in vitro, downregulating SOX2 by siRNA could counteract the effect of miR-638 inhibitor on GC cells proliferation and invasion. Our results demonstrate that miR-638 may play a pivotal role in the growth and invasion of GC.

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“…Also in the postnatal (3-week-old) pituitary, nuclear localization of YAP1 and TAZ was observed in the SOX2 + stem cell niche, and some signals were found scattered in the parenchyma (Lodge et al 2016). As SOX2 has been suggested to exert a stimulatory effect on YAP/TAZ activity in other tissues, directly by promoting Yap1 gene transcription (Seo et al 2013) and indirectly by repressing the Hippo pathway activators neurofibromin 2 (Nf2) and WW domaincontaining protein 1 (Wwc1) (Basu-Roy et al 2015), an upstream regulatory function of SOX2 in the Hippo cascade may also be assumed in the pituitary (stem cells), although this connection has still to be explored.…”

Section: Hippo Pathway: a New Player In Pituitary Stem Cell Regulation?mentioning

confidence: 99%

Pituitary stem cell regulation: who is pulling the strings?

Cox

Roose

Vennekens

et al. 2017

Journal of Endocrinology

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The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors.

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Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells

Cited by 223 publications

References 67 publications

Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

miR-488 acts as a tumor suppressor gene in gastric cancer

Pituitary stem cell regulation: who is pulling the strings?

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