The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt-PCAF pathway in promotion of esophageal squamous cell carcinoma growth
The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt-PCAF pathway in promotion of esophageal squamous cell carcinoma growth
复制标题
通过 HBXIP 激活的 Akt-PCAF 通路调节 HMGA2 乙酰化和稳定性促进食管鳞状细胞癌生长
DOI：
10.1093/nar/gkaa232
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发表时间：
2020-05-21
影响因子：
14.9
通讯作者：
Ye, Lihong
中科院分区：
文献类型：
--
作者：
Wu, Yue;Wang, Xue;Ye, Lihong
高迁移率族AT-钩2（HMGA 2）是一种结构转录因子，在胚胎发育和癌症进展中起重要作用。然而，HMGA 2调节的机制在很大程度上仍不清楚。在这里，我们证明，HMGA 2可以调制的肝炎B X相互作用蛋白（HBXIP），致癌转录辅激活因子，在食管鳞状细胞癌（ESCC）。HMGA 2表达与HBXIP表达在临床ESCC组织中呈正相关，并且其高水平与晚期肿瘤分期和总生存期和无病生存期降低相关。我们发现致癌基因HBXIP可以在ESCC细胞中上调HMGA 2蛋白水平。HBXIP诱导HMGA 2在赖氨酸26（K26）处乙酰化，导致HMGA 2蛋白积累。在此过程中，HBXIP通过Akt途径增加乙酰转移酶p300/CBP相关因子（PCAF）的磷酸化和激活，然后PCAF直接与HMGA 2相互作用，导致细胞中HMGA 2乙酰化。HMGA 2 K26乙酰化增强其DNA结合能力，阻断其泛素化，进而抑制蛋白酶体依赖性降解。在功能上，HBXIP稳定的HMGA 2可以在体外和体内促进ESCC细胞生长。引人注目的是，阿司匹林通过抑制HBXIP和HMGA 2抑制ESCC生长。总的来说，我们的研究结果揭示了一个新的机制，HMGA 2的翻译后调节HBXIP介导的食管鳞癌。
High-mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that plays essential roles in embryonic development and cancer progression. However, the mechanism of HMGA2 regulation remains largely uncharacterized. Here, we demonstrate that HMGA2 can be modulated by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, in esophageal squamous cell carcinoma (ESCC). HMGA2 expression was positively associated with HBXIP expression in clinical ESCC tissues, and their high levels were associated with advanced tumor stage and reduced overall and disease-free survival. We found that oncogenic HBXIP could posttranslationally upregulate HMGA2 protein level in ESCC cells. HBXIP induced HMGA2 acetylation at the lysine 26 (K26), resulting in HMGA2 protein accumulation. In this process, HBXIP increased the acetyltransferase p300/CBP-associated factor (PCAF) phosphorylation and activation via the Akt pathway, then PCAF directly interacted with HMGA2, leading to HMGA2 acetylation in the cells. HMGA2 K26 acetylation enhanced its DNA binding capacity and blocked its ubiquitination and then inhibited proteasome-dependent degradation. Functionally, HBXIP-stabilized HMGA2 could promote ESCC cell growth in vitro and in vivo. Strikingly, aspirin suppressed ESCC growth by inhibiting HBXIP and HMGA2. Collectively, our findings disclose a new mechanism for the posttranslational regulation of HMGA2 mediated by HBXIP in ESCC.