Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2-Hippo signaling pathway.
Clin Transl Med
; 11(8): e503, 2021 08.
Article
em En
| MEDLINE
| ID: mdl-34459131
ABSTRACT
Intrinsic resistance to CDK4/6 inhibitors hinders their clinical utility in cancer treatment. Furthermore, the predictive markers of CDK4/6 inhibitors in gastric cancer (GC) remain incompletely described. Here, we found that PAX6 expression was negatively correlated with the response to palbociclib in vitro and in vivo in GC. We observed that the PAX6 expression level was negatively correlated with the overall survival of GC patients and further showed that PAX6 can promote GC cell proliferation and the cell cycle. The cell cycle is regulated by the interaction of cyclins with their partner serine/threonine cyclin-dependent kinases (CDKs), and the G1/S-phase transition is the main target of CDK4/6 inhibitors. Therefore, we tested whether PAX6 expression was correlated with the GC response to palbociclib. We found that PAX6 hypermethylates the promoter of LATS2 and inactivates the Hippo pathway, which upregulates cyclin D1 (CCND1) expression. This results in a suppressed response to palbociclib in GC. Furthermore, we found that the induction of the Hippo signaling pathway or treatment with a DNA methylation inhibitor could overcome PAX6-induced palbociclib resistance in GC. These findings uncover a tumor promoter function of PAX6 in GC and establish overexpressed PAX6 as a mechanism of resistance to palbociclib.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Piridinas
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Neoplasias Gástricas
/
Proteínas Serina-Treonina Quinases
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Proteínas Supressoras de Tumor
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Quinase 4 Dependente de Ciclina
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Quinase 6 Dependente de Ciclina
/
Fator de Transcrição PAX6
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Via de Sinalização Hippo
Tipo de estudo:
Prognostic_studies
Limite:
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
País/Região como assunto:
Asia
Idioma:
En
Revista:
Clin Transl Med
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China