Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.
Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-me...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3677915?pdf=render |
| _version_ | 1819130401360183296 |
|---|---|
| author | Frank Götschel Daniela Berg Wolfgang Gruber Christian Bender Markus Eberl Myriam Friedel Johanna Sonntag Elena Rüngeler Hendrik Hache Christoph Wierling Wilfried Nietfeld Hans Lehrach Annemarie Frischauf Reinhard Schwartz-Albiez Fritz Aberger Ulrike Korf |
| author_facet | Frank Götschel Daniela Berg Wolfgang Gruber Christian Bender Markus Eberl Myriam Friedel Johanna Sonntag Elena Rüngeler Hendrik Hache Christoph Wierling Wilfried Nietfeld Hans Lehrach Annemarie Frischauf Reinhard Schwartz-Albiez Fritz Aberger Ulrike Korf |
| author_sort | Frank Götschel |
| collection | DOAJ |
| description | Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG) was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies. |
| first_indexed | 2024-12-22T08:59:01Z |
| format | Article |
| id | doaj.art-0d6ad5ced8ca4f8db1b89fc5e0a2ea50 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T08:59:01Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0d6ad5ced8ca4f8db1b89fc5e0a2ea502022-12-21T18:31:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6540310.1371/journal.pone.0065403Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.Frank GötschelDaniela BergWolfgang GruberChristian BenderMarkus EberlMyriam FriedelJohanna SonntagElena RüngelerHendrik HacheChristoph WierlingWilfried NietfeldHans LehrachAnnemarie FrischaufReinhard Schwartz-AlbiezFritz AbergerUlrike KorfAberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG) was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies.http://europepmc.org/articles/PMC3677915?pdf=render |
| spellingShingle | Frank Götschel Daniela Berg Wolfgang Gruber Christian Bender Markus Eberl Myriam Friedel Johanna Sonntag Elena Rüngeler Hendrik Hache Christoph Wierling Wilfried Nietfeld Hans Lehrach Annemarie Frischauf Reinhard Schwartz-Albiez Fritz Aberger Ulrike Korf Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. PLoS ONE |
| title | Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. |
| title_full | Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. |
| title_fullStr | Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. |
| title_full_unstemmed | Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. |
| title_short | Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. |
| title_sort | synergism between hedgehog gli and egfr signaling in hedgehog responsive human medulloblastoma cells induces downregulation of canonical hedgehog target genes and stabilized expression of gli1 |
| url | http://europepmc.org/articles/PMC3677915?pdf=render |
| work_keys_str_mv | AT frankgotschel synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT danielaberg synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT wolfganggruber synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT christianbender synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT markuseberl synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT myriamfriedel synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT johannasonntag synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT elenarungeler synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT hendrikhache synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT christophwierling synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT wilfriednietfeld synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT hanslehrach synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT annemariefrischauf synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT reinhardschwartzalbiez synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT fritzaberger synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 AT ulrikekorf synergismbetweenhedgehoggliandegfrsignalinginhedgehogresponsivehumanmedulloblastomacellsinducesdownregulationofcanonicalhedgehogtargetgenesandstabilizedexpressionofgli1 |