Heat Shock Protein 90α-Dependent B-Cell-2-Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto-Oncogene c-MYC mRNA Stability.
Heat Shock Protein 90α-Dependent B-Cell-2-Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto-Oncogene c-MYC mRNA Stability.
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热休克蛋白 90α-依赖 B-Cell-2-2-相关转录因子 1 通过调节 MYC Proto-Oncogene c-MYC mRNA 稳定性促进肝细胞癌增殖
DOI：
10.1002/hep.30172
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Zou F
中科院分区：
文献类型：
--
作者：
Zhou X;Wen Y;Tian Y;He M;Ke X;Huang Z;He Y;Liu L;Scharf A;Lu M;Zhang G;Deng Y;Yan Y;Mayer MP;Chen X;Zou F
B细胞淋巴瘤2(Bclaf2)相关转录因子1(Bclaf1)参与多种生物学过程，但迄今尚无证据表明Bclaf1在肝细胞癌的发生发展中起任何作用。在这里，我们证明Bclaf1在肝细胞癌中经常上调，并且Bclaf1上调与Edmondson分级、较低的总体存活率和不良预后有关。Bclaf1基因在肝癌细胞株HepG2和Huh7中过表达可显著促进细胞增殖，而Bclaf1基因下调则起到相反的作用。从Bclaf1基因敲除的Huh7细胞生长的异种移植瘤比从对照细胞生长的肿瘤体积小。此外，我们的研究将MYC原癌基因(c-Myc)描述为Bclaf1的下游靶点，因为Bclaf1通过其RS结构域在转录后调节c-MYC的表达。为了发挥这一功能，Bclaf1必须与分子伴侣热休克蛋白90α(Hsp90α)相互作用。在肝细胞癌组织标本中，Hsp90α水平也显著升高，Hsp90α与Bclaf1的相互作用增强。Bclaf1与Hsp90α的C-末端结构域相互作用，这种相互作用被C-末端结构域抑制剂novobiocin(NB)破坏，导致Bclaf1的蛋白酶体依赖的降解。此外，NB诱导的Hsp90α-Bclaf1相互作用的中断抑制了成熟c-MYC mRNA的产生，并抑制了体外和体内肿瘤细胞的生长。结论：bclaf1通过调节c-MYC mRNA的稳定性影响肝癌的进展，Hsp90α/bclaf1/c-Myc轴可能是肝癌治疗干预的潜在靶点。
B‐cell lymphoma 2 (Bcl‐2)‐associated transcription factor 1 (Bclaf1) is known to be involved in diverse biological processes, but, to date, there has been no evidence for any functional role of Bclaf1 in hepatocellular carcinoma (HCC) progression. Here, we demonstrate that Bclaf1 is frequently up‐regulated in HCC and that Bclaf1 up‐regulation is associated with Edmondson grade, lower overall survival rates, and poor prognosis. Overexpression of Bclaf1 in HCC cell lines HepG2 and Huh7 promoted proliferation considerably, whereas Bclaf1 knockdown had the opposite effect. Xenograft tumors grown from Bclaf1 knockdown Huh7 cells had smaller tumor volumes than tumors grown from control cells. Furthermore, our study describes MYC proto‐oncogene (c‐Myc) as a downstream target of Bclaf1, given that Bclaf1 regulates c‐MYC expression posttranscriptionally by its RS domain. To exert this function, Bclaf1 must interact with the molecular chaperone, heat shock protein 90 alpha (Hsp90α). In HCC tissue samples, Hsp90α levels were also increased significantly and Hsp90α‐Bclaf1 interaction was enhanced. Bclaf1 interacts with the C‐terminal domain of Hsp90α, and this interaction is disrupted by the C‐terminal domain inhibitor, novobiocin (NB), resulting in proteasome‐dependent degradation of Bclaf1. Moreover, NB‐induced disruption of Hsp90α‐Bclaf1 interaction dampened the production of mature c‐MYC mRNA and attenuated tumor cell growth in vitro and in vivo. Conclusion: Our findings suggest that Bclaf1 affects HCC progression by manipulating c‐MYC mRNA stability and that the Hsp90α/Bclaf1/c‐Myc axis might be a potential target for therapeutic intervention in HCC.
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影响因子：
5.6
作者：
Iaccarino I
通讯作者：
Iaccarino I
DOI：
10.1111/j.1432-1033.2004.04007.x
发表时间：
2004-03-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Haraguchi, T;Holaska, JM;Hiraoka, Y
通讯作者：
Hiraoka, Y
Caspase-10 在多发性骨髓瘤中控制自噬细胞死亡。
影响因子：
50.3
作者：
Lamy L;Ngo VN;Emre NC;Shaffer AL 3rd;Yang Y;Tian E;Nair V;Kruhlak MJ;Zingone A;Landgren O;Staudt LM
通讯作者：
Staudt LM
影响因子：
3
作者：
Diella F;Cameron S;Gemünd C;Linding R;Via A;Kuster B;Sicheritz-Pontén T;Blom N;Gibson TJ
通讯作者：
Gibson TJ
影响因子：
10.5
作者：
Sanford, JR;Gray, NK;Cáceres, JF
通讯作者：
Cáceres, JF