TRIB3 supports breast cancer sternness by suppressing FOXO1 degradation and enhancing SOX2 transcription
TRIB3 supports breast cancer sternness by suppressing FOXO1 degradation and enhancing SOX2 transcription
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TRIB3 通过抑制 FOXO1 降解和增强 SOX2 转录来支持乳腺癌的严重性
DOI：
10.1038/s41467-019-13700-6
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发表时间：
2019-12-16
影响因子：
16.6
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
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作者：
Yu, Jin-mei;Sun, Wei;Hu, Zhuo-Wei
乳腺癌干细胞（BCSCs）的存在是乳腺癌放化疗后转移和复发的主要原因。靶向BCSC可以改善乳腺癌复发和治疗抗性。在这里，我们报告了假激酶Tribble 3（TRIB 3）的表达与乳腺癌的干性和进展呈正相关。TRIB 3表达升高通过与AKT相互作用以干扰FOXO 1-AKT相互作用并抑制FOXO 1磷酸化、泛素化和E3连接酶SKP 2和NEDD 4L降解来支持BCSC。积累的FOXO 1促进癌症干细胞性的转录因子SOX 2的转录表达，SOX 2反过来激活FOXO 1转录并形成正调控环。在乳腺癌小鼠模型中，干扰TRIB 3-AKT相互作用通过加速FOXO 1降解和降低SOX 2表达来抑制BCSC。我们的研究提供了对乳腺癌发展的见解，并为TRIB 3过表达的乳腺癌提供了潜在的治疗策略。
The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.