PGE2-JNK signaling axis non-canonically promotes Gli activation by protecting Gli2 from ubiquitin-proteasomal degradation.
Cell Death Dis
; 12(7): 707, 2021 07 15.
Article
en En
| MEDLINE
| ID: mdl-34267186
ABSTRACT
Both bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Nucleares
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Neoplasias Colorrectales
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Dinoprostona
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Proteínas Quinasas JNK Activadas por Mitógenos
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Proteína Gli2 con Dedos de Zinc
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cell Death Dis
Año:
2021
Tipo del documento:
Article
País de afiliación:
China