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TRAF6, a key regulator of TGFβ-induced oncogenesis in prostate cancer
Umeå University, Faculty of Medicine, Department of Medical Biosciences. (Landström group)ORCID iD: 0000-0001-8737-8302
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer is the most common cancer in men, with the incidence rapidly increasing in Europe over the past two decades. Reliable biomarkers for prostate cancer are currently unavailable. Thus, there is an urgent need for improved biomarkers to diagnose prostate cancer at an early stage and to determine the best treatment options. Higher expression of transforming growth factor-β (TGFβ) has been reported in patients with aggressive cancer.

TGFβ is a multifunctional cytokine that acts as a tumor suppressor during early tumor development, and as a tumor promoter at later stages of cancer. TGFβ signals through the canonical Smad or non-Smad cascade via TGFβ type II and type I receptors. The TGFβ signaling cascade is regulated by various post-translational modifications of its key components. The present investigation aimed to identify a potential function of TRAF6 in TGFβ-induced responses in prostate cancer.

The first two articles of this thesis unveil the proteolytic cleavage of TGFβ type I receptor (TβRI), and the biological importance of the liberated TβRI intracellular domain (TβRI-ICD) in the nucleus. We found that tumor necrosis factor receptor-associated factor 6 (TRAF6) polyubiquitinates TβRI, which leads to cleavage of TβRI by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta (PKCζ)-dependent manner. Following ectodomain shedding, TβRI undergoes a second cleavage by presenilin 1 (PS1), which liberates TβRI-ICD. TβRI-ICD translocates to the nucleus, where it regulates its own expression as well as expression of the pro-invasive gene Snail1, thereby promoting invasion. We further found that TβRI-ICD associates with Notch intracellular domain (NICD) to drive expression of the pro-invasive gene Snail1, as well as Notch1 ligand Jag1.

The third article provides evidence that TRAF6 promotes Lys63-linked polyubiquitination of TβRI at Lys178 in a TGFβ-dependent manner. TβRI polyubiquitination was found to be a prerequisite for TβRI nuclear translocation, and thus for regulation of the genes involved in cell cycle, differentiation, and invasion of prostate cancer cells.

In the fourth article we investigated the role of the pro-invasive gene Snail1 in TGFβ-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2015. , 55 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1739
Keyword [en]
TβRI, TGFβ, TACE, TRAF6, PS1, PKCζ, TβRI-ICD, NICD, Smad, non-Smad, prostate cancer, Snail1, MMP, p300, p21, PAI1, ubiquitination, cleavage, ICD, invasion, HES1, signaling
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-108014ISBN: 978-91-7601-315-1 (print)OAI: oai:DiVA.org:umu-108014DiVA: diva2:850277
Public defence
2015-09-25, Hörsal Betula, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Available from: 2015-09-04 Created: 2015-09-01 Last updated: 2015-09-03Bibliographically approved
List of papers
1. TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer
Open this publication in new window or tab >>TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer
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2011 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 2, no 330, 11- p.Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGF beta binding to type II and type I serine/threonine kinase receptors (T beta RII and T beta RI) causes activation of different intracellular signaling pathways. T beta RI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGF beta, via TRAF6, causes Lys63-linked polyubiquitination of T beta RI, promoting cleavage of T beta RI by TNF-alpha converting enzyme (TACE), in a PKC zeta-dependent manner. The liberated intracellular domain (ICD) of T beta RI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGF beta-induced invasion of cancer cells is TACE- and PKC zeta-dependent and the T beta RI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for T beta RI in TGF beta mediated tumour invasion.

Place, publisher, year, edition, pages
London: Nature Publishing Group, 2011
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-47676 (URN)10.1038/ncomms1332 (DOI)000294802600035 ()
Available from: 2011-10-03 Created: 2011-09-27 Last updated: 2017-12-08Bibliographically approved
2. TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1
Open this publication in new window or tab >>TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1
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2014 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 7, no 307, ra2Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGF beta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGF beta type I receptor (T beta RI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of T beta RI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGF beta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the T beta RI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved T beta RI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, T beta RI-ICD bound to the promoter and increased the transcription of the gene encoding T beta RI. The TRAF6- and PS1-induced intramembrane proteolysis of T beta RI promoted TGF beta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-propionamide}, generation of T beta RI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2014
National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-85774 (URN)10.1126/scisignal.2004207 (DOI)000329401100004 ()
Funder
Swedish Research Council, K2010-67X-15284-01-3Swedish Cancer Society, 100303Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2014-02-13 Created: 2014-02-10 Last updated: 2017-12-06Bibliographically approved
3. TRAF6 promotes TGF beta-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGF beta type I receptor
Open this publication in new window or tab >>TRAF6 promotes TGF beta-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGF beta type I receptor
2015 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 4, 554-565 p.Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor (TGF) can act either as a tumor promoter or a tumor suppressor in a context-dependent manner. High levels of TGF are found in prostate cancer tissues and correlate with poor patient prognosis. We recently identified a novel TGF-regulated signaling cascade in which TGF type I receptor (TRI) is activated by the E3 ligase TNF-receptor-associated factor 6 (TRAF6) via the Lys63-linked polyubiquitination of TRI. TRAF6 also contributes to activation of TNF--converting enzyme and presenilin-1, resulting in the proteolytic cleavage of TRI and releasing the intracellular domain of TRI, which is translocated to the nucleus to promote tumor invasiveness. In this report, we provide evidence that Lys178 of TRI is polyubiquitinated by TRAF6. Moreover, our data suggest that TRAF6-mediated Lys63-linked ubiquitination of the TRI intracellular domain is a prerequisite for TGF regulation of mRNA for cyclin D1 (CCND1), expression, as well as for the regulation of other genes controlling the cell cycle, differentiation, and invasiveness of prostate cancer cells.

Place, publisher, year, edition, pages
Taylor & Francis, 2015
Keyword
cell cycle, cyclin D1, EMT, invasion, prostate cancer, Snail1, TRAF6, transforming growth factor beta
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-101605 (URN)10.4161/15384101.2014.990302 (DOI)000350137700018 ()25622187 (PubMedID)
Available from: 2015-04-13 Created: 2015-04-07 Last updated: 2017-12-04Bibliographically approved
4. Pro-invasive Snail1 targets TGFbeta receptor I to promote epithelial to mesenchymal transition in prostate cancer
Open this publication in new window or tab >>Pro-invasive Snail1 targets TGFbeta receptor I to promote epithelial to mesenchymal transition in prostate cancer
(English)Manuscript (preprint) (Other academic)
Keyword
Snail1
National Category
Cell and Molecular Biology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-108012 (URN)
Funder
Swedish Research CouncilSwedish Cancer SocietyKnut and Alice Wallenberg Foundation
Available from: 2015-09-01 Created: 2015-09-01 Last updated: 2015-09-03Bibliographically approved

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