SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis

被引:39
作者
Bai, Jin [1 ,2 ]
Wu, Kenneth [3 ]
Cao, Meng-Han [1 ,4 ]
Yang, Yingying [5 ]
Pan, Yu [1 ,2 ]
Liu, Hui [6 ]
He, Yizhou [7 ]
Itahana, Yoko [7 ]
Huang, Lan [5 ]
Zheng, Jun-Nian [1 ,2 ,4 ]
Pan, Zhen-Qiang [3 ]
机构
[1] Xuzhou Med Univ, Canc Inst, Jiangsu Key Lab Biol Canc, Xuzhou 221002, Jiangsu, Peoples R China
[2] Xuzhou Med Univ, Jiangsu Ctr Collaborat & Innovat Canc Biotherapy, Xuzhou 221002, Jiangsu, Peoples R China
[3] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA
[4] Xuzhou Med Univ, Affiliated Hosp, Ctr Clin Oncol, Xuzhou 221002, Jiangsu, Peoples R China
[5] Univ Calif Irvine, Dept Phys & Biophys, Irvine, CA 92697 USA
[6] Xuzhou Med Univ, Dept Pathol, Xuzhou 221002, Jiangsu, Peoples R China
[7] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Radiat Oncol, Chapel Hill, NC 27599 USA
基金
中国国家自然科学基金;
关键词
HDM2; abundance; E3; SCF-FBXO22; breast cancer metastasis; UBIQUITIN LIGASE; MDM2; PROMOTES; P53; PROTEIN; ONCOPROTEIN; E3; OVEREXPRESSION; AMPLIFICATION; INVASIVENESS; INACTIVATION;
D O I
10.1073/pnas.1820990116
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Human homolog of mouse double minute 2 (HDM2) is an oncogene frequently overexpressed in cancers with poor prognosis, but mechanisms of controlling its abundance remain elusive. In an unbiased biochemical search, we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. In human breast cancer cells, FBXO22 knockdown (KD) increased cell invasiveness, which was driven by elevated levels of HDM2. Moreover, mouse 4T1 breast tumor model studies revealed that FBXO22 KD led to a significant increase of breast tumor cell metastasis to the lung. Finally, low FBXO22 expression is correlated with worse survival and high HDM2 expression in human breast cancer. Altogether, these findings suggest that SCFFBXO22 targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis.
引用
收藏
页码:11754 / 11763
页数:10
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