A p53/lnc-Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance.
A p53/lnc-Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance.
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p53/lnc-Ip53 负反馈环调节肿瘤生长和化疗耐药
DOI：
10.1002/advs.202001364
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Zhuang SM
中科院分区：
文献类型：
--
作者：
Zhang LZ;Yang JE;Luo YW;Liu FT;Yuan YF;Zhuang SM
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. Acetylation is indispensable for activation of tumor suppressor p53. LncRNA lnc‐Ip53 is induced by p53 and in turn represses p53 acetylation by interacting with HDAC1 and p300 to prevent HDAC1 degradation and attenuate p300 activity, which consequently abrogates p53 activity and thus facilitates cell proliferation and apoptosis resistance. Abnormal upregulation of lnc‐Ip53 in tumors promotes tumor growth and confers chemoresistance.
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影响因子：
14.9
作者：
Bolognani F;Contente-Cuomo T;Perrone-Bizzozero NI
通讯作者：
Perrone-Bizzozero NI
影响因子：
64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
通讯作者：
Rinn JL
RPiRLS：RNA 与任何已知序列蛋白质相互作用的定量预测
DOI：
10.3390/molecules23030540
发表时间：
2018-02-28
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Shen WJ;Cui W;Chen D;Zhang J;Xu J
通讯作者：
Xu J
影响因子：
64.5
作者：
Bose DA;Donahue G;Reinberg D;Shiekhattar R;Bonasio R;Berger SL
通讯作者：
Berger SL
MDM2 E3连接酶介导的HDAC1在血管钙化中的泛素化和降解。
影响因子：
16.6
作者：
Kwon DH;Eom GH;Ko JH;Shin S;Joung H;Choe N;Nam YS;Min HK;Kook T;Yoon S;Kang W;Kim YS;Kim HS;Choi H;Koh JT;Kim N;Ahn Y;Cho HJ;Lee IK;Park DH;Suk K;Seo SB;Wissing ER;Mendrysa SM;Nam KI;Kook H
通讯作者：
Kook H