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Maturi, V., Morén, A., Enroth, S., Heldin, C.-H. & Moustakas, A. (2018). Genomewide binding of transcription factor Snail1 in triple-negative breast cancer cells. Molecular Oncology, 12(7), 1153-1174
Open this publication in new window or tab >>Genomewide binding of transcription factor Snail1 in triple-negative breast cancer cells
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2018 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 12, no 7, p. 1153-1174Article in journal (Refereed) Published
Abstract [en]

Transcriptional regulation mediated by the zinc finger protein Snail1 controls early embryogenesis. By binding to the epithelial tumor suppressor CDH1 gene, Snail1 initiates the epithelial-mesenchymal transition (EMT). The EMT generates stem-like cells and promotes invasiveness during cancer progression. Accordingly, Snail1 mRNA and protein is abundantly expressed in triple-negative breast cancers with enhanced metastatic potential and phenotypic signs of the EMT. Such high endogenous Snail1 protein levels permit quantitative chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. Snail1 associated with 185 genes at cis regulatory regions in the Hs578T triple-negative breast cancer cell model. These genes include morphogenetic regulators and signaling components that control polarized differentiation. Using the CRISPR/Cas9 system in Hs578T cells, a double deletion of 10bp each was engineered into the first exon and into the second exon-intron junction of Snail1, suppressing Snail1 expression and causing misregulation of several hundred genes. Specific attention to regulators of chromatin organization provides a possible link to new phenotypes uncovered by the Snail1 loss-of-function mutation. On the other hand, genetic inactivation of Snail1 was not sufficient to establish a full epithelial transition to these tumor cells. Thus, Snail1 contributes to the malignant phenotype of breast cancer cells via diverse new mechanisms.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
bone morphogenetic protein, breast cancer, chromatin immunoprecipitation, epithelial-mesenchymal transition, transforming growth factor beta
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-360496 (URN)10.1002/1878-0261.12317 (DOI)000436942300011 ()29729076 (PubMedID)
Funder
Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757Swedish National Infrastructure for Computing (SNIC), b2013260Swedish Cancer Society, CAN 2012/438Swedish Cancer Society, CAN 2015/438Swedish Cancer Society, CAN 2016/445
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Maturi, V., Enroth, S., Heldin, C.-H. & Moustakas, A. (2018). Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells. Journal of Cellular Physiology, 233(10), 7113-7127
Open this publication in new window or tab >>Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells
2018 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 233, no 10, p. 7113-7127Article in journal (Refereed) Published
Abstract [en]

Zinc finger E-box binding homeobox 1 (ZEB1) is a transcriptional regulator involved in embryonic development and cancer progression. ZEB1 induces epithelial-mesenchymal transition (EMT). Triple-negative human breast cancers express high ZEB1 mRNA levels and exhibit features of EMT. In the human triple-negative breast cancer cell model Hs578T, ZEB1 associates with almost 2,000 genes, representing many cellular functions, including cell polarity regulation (DLG2 and FAT3). By introducing a CRISPR-Cas9-mediated 30bp deletion into the ZEB1 second exon, we observed reduced migratory and anchorage-independent growth capacity of these tumor cells. Transcriptomic analysis of control and ZEB1 knockout cells, revealed 1,372 differentially expressed genes. The TIMP metallopeptidase inhibitor 3 and the teneurin transmembrane protein 2 genes showed increased expression upon loss of ZEB1, possibly mediating pro-tumorigenic actions of ZEB1. This work provides a resource for regulators of cancer progression that function under the transcriptional control of ZEB1. The data confirm that removing a single EMT transcription factor, such as ZEB1, is not sufficient for reverting the triple-negative mesenchymal breast cancer cells into more differentiated, epithelial-like clones, but can reduce tumorigenic potential, suggesting that not all pro-tumorigenic actions of ZEB1 are linked to the EMT.

Keywords
ZEB1, EMT, ChIP-seq, CRISPR-Cas9
National Category
Cell Biology
Research subject
Biochemistry; Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-334438 (URN)10.1002/jcp.26634 (DOI)000438352300071 ()29744893 (PubMedID)
Funder
Swedish Research Council, 2015-02757Swedish Research Council, K2013-66X-14936-10-5Swedish Cancer Society, CAN 2012/438Swedish Cancer Society, CAN 2015/438Swedish Cancer Society, CAN 2016/445
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-09-24Bibliographically approved
Yakymovych, I., Yakymovych, M. & Heldin, C.-H. (2018). Intracellular trafficking of transforming growth factor beta receptors. Acta biochimica et biophysica Sinica, 50(1), 3-11
Open this publication in new window or tab >>Intracellular trafficking of transforming growth factor beta receptors
2018 (English)In: Acta biochimica et biophysica Sinica, ISSN 1672-9145, Vol. 50, no 1, p. 3-11Article, review/survey (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) family members signal via heterotetrameric complexes of type I (T beta RI) and type II (T beta RII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized T beta RI and T beta RII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGF beta receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin- and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGF beta signaling, localization of the activated receptor complexes on the early endosomes promotes TGF beta-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGF beta receptors, has been shown to be required for TGF beta signaling via non-Smad pathways. The importance of proper control of TGF beta receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGF beta receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGF beta signaling.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keywords
TGF beta receptor, endocytosis, clathrin, lipid rafts, endosome
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-350115 (URN)10.1093/abbs/gmx119 (DOI)000423304200002 ()29186283 (PubMedID)
Available from: 2018-05-07 Created: 2018-05-07 Last updated: 2018-05-07Bibliographically approved
Heldin, C.-H., Lennartsson, J. & Westermark, B. (2018). Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. Journal of Internal Medicine, 283(1), 16-44
Open this publication in new window or tab >>Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis
2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 1, p. 16-44Article, review/survey (Refereed) Published
Abstract [en]

Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins ofthe receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.

Keywords
inhibitor, kinase, malignancy, receptor, signal transduction, PDGF
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-347709 (URN)10.1111/joim.12690 (DOI)000418411100002 ()28940884 (PubMedID)
Funder
Swedish Cancer Society, 2016/445; 2015/226; 2014/468Swedish Research Council, 2015-02757
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-04-06Bibliographically approved
Sundqvist, A., Morikawa, M., Ren, J., Vasilaki, E., Kawasaki, N., Kobayashi, M., . . . ten Dijke, P. (2018). JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion. Nucleic Acids Research, 46(3), 1180-1195
Open this publication in new window or tab >>JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 3, p. 1180-1195Article in journal (Refereed) Published
Abstract [en]

It is well established that transforming growth factor-beta (TGF beta) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD and other transcription factors define pro-oncogenic events. Here, we have performed chromatin immunoprecipitation (ChIP)-sequencing analyses which indicate that the genome-wide landscape of SMAD2/3 binding is altered after prolonged TGF beta stimulation. De novo motif analyses of the SMAD2/3 binding regions predict enrichment of binding motifs for activator protein (AP) 1 in addition to SMAD motifs. TGF beta-induced expression of the AP1 component JUNB was required for expression of many late invasion-mediating genes, creating a feed-forward regulatory network. Moreover, we found that several components in the WNT pathway were enriched among the late TGF beta-target genes, including the invasion-inducing WNT7 proteins. Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGF beta-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process. Our study thereby helps to explain how accumulation of pro-oncogenic stimuli switches and stabilizes TGF beta-induced cellular phenotypes of epithelial cells.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-349356 (URN)10.1093/nar/gkx1190 (DOI)000425294400020 ()29186616 (PubMedID)
Funder
Swedish Cancer Society, 09 0773, 10 0452, 2016/445Swedish Research Council, 2015-02757
Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-05-02Bibliographically approved
Papadopoulos, N., Lennartsson, J. & Heldin, C.-H. (2018). PDGFR beta translocates to the nucleus and regulates chromatin remodeling via TATA element-modifying factor 1. Journal of Cell Biology, 217(5), 1701-1717
Open this publication in new window or tab >>PDGFR beta translocates to the nucleus and regulates chromatin remodeling via TATA element-modifying factor 1
2018 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 217, no 5, p. 1701-1717Article in journal (Refereed) Published
Abstract [en]

Translocation of full-length or fragments of receptors to the nucleus has been reported for several tyrosine kinase receptors. In this paper, we show that a fraction of full-length cell surface platelet-derived growth factor (PDGF) receptor beta (PDG FR beta) accumulates in the nucleus at the chromatin and the nuclear matrix after ligand stimulation. Nuclear translocation of PDG FR beta was dependent on PDGF-BB-induced receptor dimerization, clathrin-mediated endocytosis, beta-importin, and intact Golgi, occurring in both normal and cancer cells. In the nucleus, PDG FR beta formed ligand-inducible complexes with the tyrosine kinase Fer and its substrate, TATA element-modifying factor 1 (TMF-1). PDGF-BB stimulation decreased TMF-1 binding to the transcriptional regulator Brahma-related gene 1 (Brg-1) and released Brg-1 from the SWI-SNF chromatin remodeling complex. Moreover, knockdown of TMF-1 by small interfering RNA decreased nuclear translocation of PDG FR beta and caused significant up-regulation of the Brg-1/p53-regulated cell cycle inhibitor CDKN1A (encoding p21) without affecting PDG FR beta-inducible immediate-early genes. In conclusion, nuclear interactions of PDG FR beta control proliferation by chromatin remodeling and regulation of p21 levels.

Place, publisher, year, edition, pages
ROCKEFELLER UNIV PRESS, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-356403 (URN)10.1083/jcb.201706118 (DOI)000431616300016 ()29545370 (PubMedID)
Funder
Swedish Research Council, 2015-02757Swedish Cancer Society, 2016/445Swedish Cancer Society, 140332
Available from: 2018-07-25 Created: 2018-07-25 Last updated: 2018-07-25Bibliographically approved
Bellomo, C., Caja, L., Fabregat, I., Mikulits, W., Kardassis, D., Heldin, C.-H. & Moustakas, A. (2018). Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma. Cell Death and Differentiation, 25(5), 885-903
Open this publication in new window or tab >>Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
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2018 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 25, no 5, p. 885-903Article in journal (Refereed) Published
Abstract [en]

Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.

National Category
Medical and Health Sciences Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-339262 (URN)10.1038/s41418-017-0021-3 (DOI)000431770600007 ()29230000 (PubMedID)
Funder
Swedish Cancer Society, CAN 2012/438; CAN 2015/438; CAN 2016/445; CAN 2012/1186Swedish Research Council, K2013-66X-14936-10-5; 2015-02757
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-12-03Bibliographically approved
Caja, L., Tzavlaki, K., Dadras, M. S., Tan, E.-J., Hatem, G., Maturi, N. P., . . . Moustakas, A. (2018). Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells. Oncogene, 37(19), 2515-2531
Open this publication in new window or tab >>Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells
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2018 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 19, p. 2515-2531Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor beta (TGF beta) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGF beta 1 signaling activity. Exogenous TGF beta 1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGF beta pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-355463 (URN)10.1038/s41388-018-0136-0 (DOI)000431873400005 ()29449696 (PubMedID)
Funder
Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757
Note

Andra och tredje författare delar andra författarskapet.

Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-12-03Bibliographically approved
Mehic, M. S., de Sa, V. K., Hebestreit, S., Heldin, P. & Heldin, C.-H. S. (2018). The role of deubiquitinating enzyme USP17, hyaluronan synthase 2, and hyaluronan in non-small-cell lung cancer oncogenic transformation. Paper presented at International Conference of the American-Association-for-Cancer-Research (AACR), MAY 04-06, 2017, Sao Paulo, BRAZIL. Clinical Cancer Research, 24(1), 96-96
Open this publication in new window or tab >>The role of deubiquitinating enzyme USP17, hyaluronan synthase 2, and hyaluronan in non-small-cell lung cancer oncogenic transformation
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2018 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 1, p. 96-96Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Lung cancer is the result of a multistep accumulation of genetic and/or epigenetic alterations; therefore, a better understanding of the molecular mechanism by which these alterations affect lung cancer pathogenesis would provide new diagnostic procedures and prognostic factors for early detection of recurrence. The remarkable qualitative and quantitative modifications of extracellular matrix components as the deubiquitinating enzyme (USP17), hyaluronan (HA), and hyaluronan synthases 2 (HAS 2) may favor invasion, cellular motility, and proliferation in several cancers including lung.

Results: The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis. Importantly, high levels of USP17 and HAS2 were detected in a panel of cancer cell lines compared to normal cells, and immunohistochemical stainings revealed higher expression of USP17 and HAS2 in tissues of lung cancer patients compared to normal tissue. Numerous epithelial cells expressed USP17 and HAS2 in dysplasia compared to squamous cell carcinoma (SqCC) (p=0.001). USP17 and HAS2 were prominently expressed in adenocarcinoma (ADC) (p≤0.005). HA immunostaining indexes were increased in ADC and SqCC compared to normal and dysplasia cells (p=0.05). Consistent with the immunohistochemical analyses, low amounts of hyaluronan and USP17 were observed in SqCC by confocal analysis, coincident with less colocalization as determined by confocal microscopy. In contrast, a high expression of hyaluronan (48% of positive index) and high USP17 expression (78% of positive index) in ADC was consistent with a higher degree of colocalization.

Conclusions: HAS2, hyaluronan and USP17 were expressed at higher levels in particular in preneoplastic lesions and ADC, suggesting a role in NSCLC oncogenic transformation, possibly by promoting cellular division by USP17-mediated. Elucidation of the mechanism of how USP17 and HAS2 cooperate in the regulation of the cell cycle might be of therapeutic importance.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-347110 (URN)10.1158/1557-3265.TCM17-B64 (DOI)000419180000165 ()
Conference
International Conference of the American-Association-for-Cancer-Research (AACR), MAY 04-06, 2017, Sao Paulo, BRAZIL
Available from: 2018-03-26 Created: 2018-03-26 Last updated: 2018-03-26Bibliographically approved
Papoutsoglou, P., Tsubakihara, Y., Caja, L., Pallis, P., Ameur, A., Heldin, C.-H. & Moustakas, A. (2018). The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity.
Open this publication in new window or tab >>The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity
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2018 (English)Article in journal (Refereed) Submitted
Abstract [en]

LncRNAs regulate cell function through many physiological processes. We have identified lncRNAs whose expression is regulated by transforming growth factor β (TGFβ), by a transcriptomic screen. We focused on TGFB2-antisense RNA1 (TGFB2-AS1), which was induced by TGFβ through Smad and protein kinase pathways, and exhibited predominantly nuclear localization. Depleting TGFB2-AS1 enhanced TGFβ/Smad-mediated transcription and expression of the TGFβ-target genes FN1 and SERPINE1. Overexpression of TGFB2-AS1 reduced expression of these genes, attenuated TGFβ-induced cell growth arrest, and altered BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1 mainly via its 3’ terminal region, bound to EED, an adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me3 modifications at TGFβ-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity, partially rescued TGFB2-AS1 mediated gene repression. Our observations support the notion that TGFB2-AS1 is a TGFβ-induced lncRNA with inhibitory functions on TGFβ and BMP pathways output, constituting an auto-regulatory negative feedback mechanism that balances TGFβ- and BMP-mediated responses.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-363700 (URN)
Available from: 2018-10-20 Created: 2018-10-20 Last updated: 2018-12-03
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9508-896x

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