A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance
Abstract Acetylation is a critical mechanism to modulate tumor‐suppressive activity of p53, but the causative roles of long non‐coding RNAs (lncRNAs) in p53 acetylation and their biological significance remain unexplored. Here, lncRNA LOC100294145 is discovered to be transactivated by p53 and is thu...
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doaj-2a7d094d8d6341c29dd5fd0330a8345c2020-11-25T04:03:59ZengWileyAdvanced Science2198-38442020-11-01721n/an/a10.1002/advs.202001364A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and ChemoresistanceLi‐Zhen Zhang0Jin‐E Yang1Yu‐Wei Luo2Feng‐Ting Liu3Yun‐Fei Yuan4Shi‐Mei Zhuang5MOE Key Laboratory of Gene Function and Regulation School of Life Sciences Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Guangzhou 510275 ChinaMOE Key Laboratory of Gene Function and Regulation School of Life Sciences Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Guangzhou 510275 ChinaMOE Key Laboratory of Gene Function and Regulation School of Life Sciences Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Guangzhou 510275 ChinaMOE Key Laboratory of Gene Function and Regulation School of Life Sciences Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Guangzhou 510275 ChinaDepartment of Hepatobilliary Oncology Cancer Center Sun Yat‐sen University Guangzhou 510060 ChinaMOE Key Laboratory of Gene Function and Regulation School of Life Sciences Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Guangzhou 510275 ChinaAbstract Acetylation is a critical mechanism to modulate tumor‐suppressive activity of p53, but the causative roles of long non‐coding RNAs (lncRNAs) in p53 acetylation and their biological significance remain unexplored. Here, lncRNA LOC100294145 is discovered to be transactivated by p53 and is thus designated as lnc‐Ip53 for lncRNA induced by p53. Furthermore, lnc‐Ip53 impedes p53 acetylation by interacting with histone deacetylase 1 (HDAC1) and E1A binding protein p300 (p300) to prevent HDAC1 degradation and attenuate p300 activity, resulting in abrogation of p53 activity and subsequent cell proliferation and apoptosis resistance. Mouse xenograft models reveal that lnc‐Ip53 promotes tumor growth and chemoresistance in vivo, which is attenuated by an HDAC inhibitor. Silencing lnc‐Ip53 inhibits the growth of xenografts with wild‐type p53, but not those expressing acetylation‐resistant p53. Consistently, lnc‐Ip53 is upregulated in multiple cancer types, including hepatocellular carcinoma (HCC). High levels of lnc‐Ip53 is associated with low levels of acetylated p53 in human HCC and mouse xenografts, and is also correlated with poor survival of HCC patients. These findings identify a novel p53/lnc‐Ip53 negative feedback loop in cells and indicate that abnormal upregulation of lnc‐Ip53 represents an important mechanism to inhibit p53 acetylation/activity and thereby promote tumor growth and chemoresistance, which may be exploited for anticancer therapy.https://doi.org/10.1002/advs.202001364acetylationlnc‐Ip53non‐coding RNAp53tumor growth |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Li‐Zhen Zhang Jin‐E Yang Yu‐Wei Luo Feng‐Ting Liu Yun‐Fei Yuan Shi‐Mei Zhuang |
spellingShingle |
Li‐Zhen Zhang Jin‐E Yang Yu‐Wei Luo Feng‐Ting Liu Yun‐Fei Yuan Shi‐Mei Zhuang A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance Advanced Science acetylation lnc‐Ip53 non‐coding RNA p53 tumor growth |
author_facet |
Li‐Zhen Zhang Jin‐E Yang Yu‐Wei Luo Feng‐Ting Liu Yun‐Fei Yuan Shi‐Mei Zhuang |
author_sort |
Li‐Zhen Zhang |
title |
A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance |
title_short |
A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance |
title_full |
A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance |
title_fullStr |
A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance |
title_full_unstemmed |
A p53/lnc‐Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance |
title_sort |
p53/lnc‐ip53 negative feedback loop regulates tumor growth and chemoresistance |
publisher |
Wiley |
series |
Advanced Science |
issn |
2198-3844 |
publishDate |
2020-11-01 |
description |
Abstract Acetylation is a critical mechanism to modulate tumor‐suppressive activity of p53, but the causative roles of long non‐coding RNAs (lncRNAs) in p53 acetylation and their biological significance remain unexplored. Here, lncRNA LOC100294145 is discovered to be transactivated by p53 and is thus designated as lnc‐Ip53 for lncRNA induced by p53. Furthermore, lnc‐Ip53 impedes p53 acetylation by interacting with histone deacetylase 1 (HDAC1) and E1A binding protein p300 (p300) to prevent HDAC1 degradation and attenuate p300 activity, resulting in abrogation of p53 activity and subsequent cell proliferation and apoptosis resistance. Mouse xenograft models reveal that lnc‐Ip53 promotes tumor growth and chemoresistance in vivo, which is attenuated by an HDAC inhibitor. Silencing lnc‐Ip53 inhibits the growth of xenografts with wild‐type p53, but not those expressing acetylation‐resistant p53. Consistently, lnc‐Ip53 is upregulated in multiple cancer types, including hepatocellular carcinoma (HCC). High levels of lnc‐Ip53 is associated with low levels of acetylated p53 in human HCC and mouse xenografts, and is also correlated with poor survival of HCC patients. These findings identify a novel p53/lnc‐Ip53 negative feedback loop in cells and indicate that abnormal upregulation of lnc‐Ip53 represents an important mechanism to inhibit p53 acetylation/activity and thereby promote tumor growth and chemoresistance, which may be exploited for anticancer therapy. |
topic |
acetylation lnc‐Ip53 non‐coding RNA p53 tumor growth |
url |
https://doi.org/10.1002/advs.202001364 |
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