Acetylation of Checkpoint suppressor 1 enhances its stability and promotes the progression of triple-negative breast cancer.
Acetylation of Checkpoint suppressor 1 enhances its stability and promotes the progression of triple-negative breast cancer.
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检查点抑制因子1的乙酰化增强其稳定性并促进三阴性乳腺癌的进展
DOI：
10.1038/s41420-022-01269-x
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发表时间：
2022-12-01
影响因子：
7
通讯作者：
Tian, Geng
中科院分区：
文献类型：
--
作者：
Xu, Zhaowei;Liu, Shuyan;Feng, Chun;Xu, Fuyi;Kong, Demin;Mi, Jia;Yang, Chunhua;Zhang, Guilong;Wei, Pengfei;Orgil, Buyan-Ochir;Bergquist, Jonas;Tian, Geng
检查点抑制因子1（Checkpoint suppressor 1，CHES 1）是一种转录调控因子，在包括乳腺癌在内的多种恶性肿瘤中表达异常，其表达水平与患者的病情进展和预后密切相关。然而，CHES 1在乳腺癌中表达的潜在调控机制以及翻译后修饰（PTM）对其功能表现的影响仍有待充分研究。在此，我们发现CHES 1在三阴性乳腺癌（TNBC）中具有高丰度，并且其表达与恶性表型和患者的不良预后密切相关。进一步证实CHES 1是一种乙酰化蛋白，其动态修饰由p300和HDAC 1介导，乙酰化通过降低其泛素化和降解增强其稳定性，从而导致CHES 1在TNBC中的高丰度。RNA-seq和功能研究表明，CHES 1促进了致癌基因的激活和导致TNBC增殖和转移的途径。综上所述，本研究建立了乙酰化对CHES 1稳定性和活性的新的调节作用。这些结果表明CHES 1乙酰化在TNBC进展中的重要性及其潜在机制，为乳腺癌的分子靶向治疗提供了新的潜在候选者。
Checkpoint suppressor 1 (CHES1), a transcriptional regulator, had been dysregulated in many types of malignancies including breast cancer, and its expression level is strongly associated with progression and prognosis of patients. However, the underlying regulatory mechanisms of CHES1 expression in the breast cancer and the effects of post-translational modifications (PTMs) on its functional performance remain to be fully investigated. Herein, we found that CHES1 had a high abundance in triple-negative breast cancer (TNBC) and its expression was tightly associated with malignant phenotype and poor outcomes of patients. Furthermore, we confirmed that CHES1 was an acetylated protein and its dynamic modification was mediated by p300 and HDAC1, and CHES1 acetylation enhanced its stability via decreasing its ubiquitination and degradation, which resulted in the high abundance of CHES1 in TNBC. RNA-seq and functional study revealed that CHES1 facilitated the activation of oncogenic genes and pathways leading to proliferation and metastasis of TNBC. Taken together, this research established a novel regulatory role of acetylation on the stability and activity of CHES1. The results demonstrate the significance of CHES1 acetylation and underlying mechanisms in the progression of TNBC, offering new potential candidate for molecular-targeted therapy in breast cancer.
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影响因子：
--
作者：
Whitney EM;Ghaleb AM;Chen X;Yang VW
通讯作者：
Yang VW
影响因子：
8.8
作者：
Karanth S;Zinkhan EK;Hill JT;Yost HJ;Schlegel A
通讯作者：
Schlegel A
影响因子：
7.3
作者：
Ho, Terence C. S.;Chan, Alex H. Y.;Ganesan, A.
通讯作者：
Ganesan, A.
DOI：
10.1073/pnas.1310430110
发表时间：
2013-07-23
影响因子：
11.1
作者：
Nakagawa, So;Gisselbrecht, Stephen S.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
11.2
作者：
Mudduluru, Giridhar;Abba, Mohammed;Allgayer, Heike
通讯作者：
Allgayer, Heike