PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing
Abstract Alternative splicing (AS) and the regulation of AS by splicing factors play critical roles in cancer. Plant homeodomain (PHD)–finger domain protein PHF5A, a critical splicing factor involved in AS, has been demonstrated to play an oncogenic role in glioblastoma multiforme and breast cancer,...
Main Authors: | , , , , , , , , , , , |
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Format: | Article |
Language: | English |
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Wiley
2019-05-01
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Series: | Cancer Medicine |
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Online Access: | https://doi.org/10.1002/cam4.2115 |
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doaj-697c203cca1e4252907df9b369ec9643 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shuangshuang Mao Yuan Li Zhiliang Lu Yun Che Jianbing Huang Yuanyuan Lei Yalong Wang Chengming Liu Xinfeng Wang Sufei Zheng Nan Sun Jie He |
spellingShingle |
Shuangshuang Mao Yuan Li Zhiliang Lu Yun Che Jianbing Huang Yuanyuan Lei Yalong Wang Chengming Liu Xinfeng Wang Sufei Zheng Nan Sun Jie He PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing Cancer Medicine alternative splicing lung adenocarcinoma PHF5A splicing factor |
author_facet |
Shuangshuang Mao Yuan Li Zhiliang Lu Yun Che Jianbing Huang Yuanyuan Lei Yalong Wang Chengming Liu Xinfeng Wang Sufei Zheng Nan Sun Jie He |
author_sort |
Shuangshuang Mao |
title |
PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing |
title_short |
PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing |
title_full |
PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing |
title_fullStr |
PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing |
title_full_unstemmed |
PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing |
title_sort |
phd finger protein 5a promoted lung adenocarcinoma progression via alternative splicing |
publisher |
Wiley |
series |
Cancer Medicine |
issn |
2045-7634 |
publishDate |
2019-05-01 |
description |
Abstract Alternative splicing (AS) and the regulation of AS by splicing factors play critical roles in cancer. Plant homeodomain (PHD)–finger domain protein PHF5A, a critical splicing factor involved in AS, has been demonstrated to play an oncogenic role in glioblastoma multiforme and breast cancer, but its biological function in lung cancer remains unclear. In the present study, we systematically analyzed the biological function and clinical relevance of PHF5A in non–small cell lung cancer (NSCLC). We found that PHF5A was significantly upregulated in NSCLC tumors compared with normal tissues in both TCGA data set and tissue microarrays. Upregulation of PHF5A was negatively correlated to the overall survival (OS) of lung adenocarcinoma (LUAD) patients. Loss‐of‐function and gain‐of‐function experiments confirmed that PHF5A functioned as an oncoprotein by promoting LUAD cell proliferation, migration and invasion, inducing G0/G1 cell cycle progression and inhibiting cisplatin–induced apoptosis. RNA–seq analysis identified many essential genes whose AS was dysregulated by PHF5A, including cell cycle–associated genes such as SKP2, CHEK2, ATR and apoptosis–associated genes such as API5 and BCL2L13. Additionally, pladienolide, a small molecular inhibitor of PHF5A, inhibited LUAD cell proliferation in a dose–dependent manner and induced AS changes similar to PHF5A knockdown. In conclusion, we validated that PHF5A played an oncogenic role via AS in LUAD and suggested that PHF5A might serve as a potential drug target with a promising anticancer therapeutic effect. |
topic |
alternative splicing lung adenocarcinoma PHF5A splicing factor |
url |
https://doi.org/10.1002/cam4.2115 |
work_keys_str_mv |
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doaj-697c203cca1e4252907df9b369ec96432020-11-24T21:26:28ZengWileyCancer Medicine2045-76342019-05-01852429244110.1002/cam4.2115PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicingShuangshuang Mao0Yuan Li1Zhiliang Lu2Yun Che3Jianbing Huang4Yuanyuan Lei5Yalong Wang6Chengming Liu7Xinfeng Wang8Sufei Zheng9Nan Sun10Jie He11Department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaAbstract Alternative splicing (AS) and the regulation of AS by splicing factors play critical roles in cancer. Plant homeodomain (PHD)–finger domain protein PHF5A, a critical splicing factor involved in AS, has been demonstrated to play an oncogenic role in glioblastoma multiforme and breast cancer, but its biological function in lung cancer remains unclear. In the present study, we systematically analyzed the biological function and clinical relevance of PHF5A in non–small cell lung cancer (NSCLC). We found that PHF5A was significantly upregulated in NSCLC tumors compared with normal tissues in both TCGA data set and tissue microarrays. Upregulation of PHF5A was negatively correlated to the overall survival (OS) of lung adenocarcinoma (LUAD) patients. Loss‐of‐function and gain‐of‐function experiments confirmed that PHF5A functioned as an oncoprotein by promoting LUAD cell proliferation, migration and invasion, inducing G0/G1 cell cycle progression and inhibiting cisplatin–induced apoptosis. RNA–seq analysis identified many essential genes whose AS was dysregulated by PHF5A, including cell cycle–associated genes such as SKP2, CHEK2, ATR and apoptosis–associated genes such as API5 and BCL2L13. Additionally, pladienolide, a small molecular inhibitor of PHF5A, inhibited LUAD cell proliferation in a dose–dependent manner and induced AS changes similar to PHF5A knockdown. In conclusion, we validated that PHF5A played an oncogenic role via AS in LUAD and suggested that PHF5A might serve as a potential drug target with a promising anticancer therapeutic effect.https://doi.org/10.1002/cam4.2115alternative splicinglung adenocarcinomaPHF5Asplicing factor |