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Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382979/ https://www.ncbi.nlm.nih.gov/pubmed/34459131 http://dx.doi.org/10.1002/ctm2.503 |
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author | Zhang, Yi He, Long‐Jun Huang, Lin‐Lin Yao, Sheng Lin, Nan Li, Ping Xu, Hui‐Wen Wu, Xi‐Wen Xu, Jian‐Liang Lu, Yi Li, Yan‐Jie Zhu, Sen‐Lin |
author_facet | Zhang, Yi He, Long‐Jun Huang, Lin‐Lin Yao, Sheng Lin, Nan Li, Ping Xu, Hui‐Wen Wu, Xi‐Wen Xu, Jian‐Liang Lu, Yi Li, Yan‐Jie Zhu, Sen‐Lin |
author_sort | Zhang, Yi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8382979 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83829792021-08-30 Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway Zhang, Yi He, Long‐Jun Huang, Lin‐Lin Yao, Sheng Lin, Nan Li, Ping Xu, Hui‐Wen Wu, Xi‐Wen Xu, Jian‐Liang Lu, Yi Li, Yan‐Jie Zhu, Sen‐Lin Clin Transl Med Research Articles 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. John Wiley and Sons Inc. 2021-08-23 /pmc/articles/PMC8382979/ /pubmed/34459131 http://dx.doi.org/10.1002/ctm2.503 Text en © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Zhang, Yi He, Long‐Jun Huang, Lin‐Lin Yao, Sheng Lin, Nan Li, Ping Xu, Hui‐Wen Wu, Xi‐Wen Xu, Jian‐Liang Lu, Yi Li, Yan‐Jie Zhu, Sen‐Lin Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway |
title | Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway |
title_full | Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway |
title_fullStr | Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway |
title_full_unstemmed | Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway |
title_short | Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway |
title_sort | oncogenic pax6 elicits cdk4/6 inhibitor resistance by epigenetically inactivating the lats2‐hippo signaling pathway |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382979/ https://www.ncbi.nlm.nih.gov/pubmed/34459131 http://dx.doi.org/10.1002/ctm2.503 |
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