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Tsubakihara, Yutaro
Publications (5 of 5) Show all publications
Morén, A., Bellomo, C., Tsubakihara, Y., Kardassis, D., Mikulits, W., Heldin, C.-H. & Moustakas, A. (2019). LXR alpha limits TGF beta-dependent hepatocellular carcinoma associated fibroblast differentiation. Oncogenesis, 8, Article ID 36.
Open this publication in new window or tab >>LXR alpha limits TGF beta-dependent hepatocellular carcinoma associated fibroblast differentiation
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2019 (English)In: Oncogenesis, E-ISSN 2157-9024, Vol. 8, article id 36Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGF beta and undergo myofibroblastic differentiation during tissue wound healing and cancer progression. Cancer-associated fibroblasts (CAFs) communicate with tumor cells during cancer progression, under the guidance of TGF beta signaling. We report that agonist-activated liver X receptors (LXR) limit the expression of key components of myofibroblast differentiation, including the a-smooth muscle actin (alpha SMA) gene in liver cancer cells. CAFs derived from hepatocellular carcinoma (HCC) express high aSMA and low LXR alpha levels, whereas hepatocarcinoma cells exhibit an inverse expression pattern. All hepatoma cells analyzed responded to the LXR alpha agonist T0901317 by inducing fatty acid synthase (FASN) expression. On the other hand, T0901317 antagonized TGF beta-induced fibroblastic marker responses, such as fibronectin and calponin, in a subset of hepatoma cells and all CAFs analyzed. Mechanistically, LXR alpha antagonized TGF beta signaling at the transcriptional level. Smad3 and LXR alpha were recruited to adjacent DNA motifs of the ACTA2 promoter. Upon cloning the human ACTA2 promoter, we confirmed its transcriptional induction by TGF beta stimulation, and LXR alpha overexpression repressed the promoter activity. Hepatosphere formation by HCC cells was enhanced upon co-culturing with CAFs. T0901317 suppressed the positive effects exerted on hepatosphere growth by CAFs. Taken together, the data suggest that LXR alpha agonists limit TGF beta-dependent CAF differentiation, potentially limiting primary HCC growth.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-387277 (URN)10.1038/s41389-019-0140-4 (DOI)000468075200001 ()31097694 (PubMedID)
Funder
Swedish Research Council, K2013-66 x - 14936-10-5Swedish Research Council, 2017-01588Swedish Research Council, 2018-02757Swedish Research Council, 2015-02757EU, FP7, Seventh Framework ProgrammeEU, European Research Council, 787472
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Papoutsoglou, P., Tsubakihara, Y., Caja, L., Morén, A., Pallis, P., Ameur, A., . . . Moustakas, A. (2019). The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity. Cell reports, 28(12), 3182-3198.ell
Open this publication in new window or tab >>The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 28, no 12, p. 3182-3198.ellArticle in journal (Refereed) Published
Abstract [en]

Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor beta (TGF-beta). Upon silencing individual lncRNAs, we identify several that regulate TGF-beta signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-beta through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-beta/Smad-mediated transcription and expression of hallmark TGF-beta-target genes. Increased dose of TGFB2-AS1 reduces expression of these genes, attenuates TGF-beta-induced cell growth arrest, and alters BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1, mainly via its 3' terminal region, binds to the EED adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me(3) modifications at TGF-beta-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity partially rescues TGFB2-AS1-mediated gene repression. Thus, the TGF-beta-induced TGFB2-AS1 lncRNA exerts inhibitory functions on TGF-beta/BMP signaling output, supporting auto-regulatory negative feedback that balances TGF-beta/BMP-mediated responses.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-395306 (URN)10.1016/j.celrep.2019.08.028 (DOI)000486389400014 ()31533040 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/438Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757EU, European Research Council, 787472
Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-18Bibliographically approved
Tsubakihara, Y. & Moustakas, A. (2018). Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor. International Journal of Molecular Sciences, 19(11), Article ID 3672.
Open this publication in new window or tab >>Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor
2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 11, article id 3672Article, review/survey (Refereed) Published
Abstract [en]

Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor (TGF). The power of TGF to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGF, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGF signaling and EMT facilitate tumor cell dissemination.

Keywords
epithelial-mesenchymal transition, micro-RNA, non-coding RNA, signal transduction, transcription factor, transforming growth factor, tumor invasiveness
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-372518 (URN)10.3390/ijms19113672 (DOI)000451528500388 ()30463358 (PubMedID)
Funder
Swedish Research Council, K2013-66X-14936-10-5
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically 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
Watanabe, Y., Papoutsoglou, P., Maturi, V., Tsubakihara, Y., Hottiger, M. O., Heldin, C.-H. & Moustakas, A. (2016). Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation. Journal of Biological Chemistry, 291(24), 12706-12723
Open this publication in new window or tab >>Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 24, p. 12706-12723Article in journal (Refereed) Published
Abstract [en]

We previously established a mechanism of negative regulation of transforming growth factor beta signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4. The positive role PARG plays during BMP signaling can be neutralized by PARP1, as demonstrated by experiments where PARG and PARP1 are simultaneously silenced. In contrast to PARG, ectopic expression of PARP1 suppresses BMP signaling, whereas silencing of endogenous PARP1 enhances signaling and BMP-induced differentiation. The two major Smad proteins of the BMP pathway, Smad1 and Smad5, interact with PARP1 and can be ADP-ribosylated in vitro, whereas PARG causes deribosylation. The overall outcome of this mode of regulation of BMP signal transduction provides a fine-tuning mechanism based on the two major enzymes that control cellular ADP-ribosylation.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-299724 (URN)10.1074/jbc.M116.729699 (DOI)000378119900024 ()27129221 (PubMedID)
Funder
Swedish Research Council, K2010-67X-14936-07-3 K2013-66X-14936-10-5
Available from: 2016-07-26 Created: 2016-07-26 Last updated: 2018-10-23Bibliographically approved
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