Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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
_version_ 1783741646752448512
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
work_keys_str_mv AT zhangyi oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT helongjun oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT huanglinlin oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT yaosheng oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT linnan oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT liping oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT xuhuiwen oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT wuxiwen oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT xujianliang oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT luyi oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT liyanjie oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway
AT zhusenlin oncogenicpax6elicitscdk46inhibitorresistancebyepigeneticallyinactivatingthelats2hipposignalingpathway