PMID- 31138683 OWN - NLM STAT- MEDLINE DCOM- 20200324 LR - 20200324 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 116 IP - 24 DP - 2019 Jun 11 TI - SCF(FBXO22) targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis. PG - 11754-11763 LID - 10.1073/pnas.1820990116 [doi] AB - 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 (SCF(FBXO22)) 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 SCF(FBXO22) targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis. FAU - Bai, Jin AU - Bai J AD - Jiangsu Key Laboratory of Biological Cancer, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China; bj@xzhmu.edu.cn jnzheng@xzhmu.edu.cn zhen-qiang.pan@mssm.edu. AD - Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, China. FAU - Wu, Kenneth AU - Wu K AD - Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574. FAU - Cao, Meng-Han AU - Cao MH AD - Jiangsu Key Laboratory of Biological Cancer, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China. AD - Center of Clinical Oncology, Affiliated Hospital, Xuzhou Medical University, Xuzhou 221002, China. FAU - Yang, Yingying AU - Yang Y AD - Department of Physiology and Biophysics, University of California, Irvine, CA 92697. FAU - Pan, Yu AU - Pan Y AD - Jiangsu Key Laboratory of Biological Cancer, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China. AD - Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, China. FAU - Liu, Hui AU - Liu H AD - Department of Pathology, Xuzhou Medical University, Xuzhou 221002 China. FAU - He, Yizhou AU - He Y AD - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. FAU - Itahana, Yoko AU - Itahana Y AUID- ORCID: 0000-0003-3560-4560 AD - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. FAU - Huang, Lan AU - Huang L AD - Department of Physiology and Biophysics, University of California, Irvine, CA 92697. FAU - Zheng, Jun-Nian AU - Zheng JN AD - Jiangsu Key Laboratory of Biological Cancer, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China; bj@xzhmu.edu.cn jnzheng@xzhmu.edu.cn zhen-qiang.pan@mssm.edu. AD - Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, China. AD - Center of Clinical Oncology, Affiliated Hospital, Xuzhou Medical University, Xuzhou 221002, China. FAU - Pan, Zhen-Qiang AU - Pan ZQ AD - Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574; bj@xzhmu.edu.cn jnzheng@xzhmu.edu.cn zhen-qiang.pan@mssm.edu. LA - eng GR - R01 GM061051/GM/NIGMS NIH HHS/United States GR - R01 GM074830/GM/NIGMS NIH HHS/United States GR - R01 GM122751/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190528 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (F-Box Proteins) RN - 0 (FBXO22 protein, human) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Cytoplasmic and Nuclear) RN - 0 (Ubiquitin) RN - EC 2.3.2.27 (MDM2 protein, human) RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Animals MH - Breast Neoplasms/*metabolism/*pathology MH - Cell Line, Tumor MH - Cell Movement/*physiology MH - F-Box Proteins/*metabolism MH - Female MH - HCT116 Cells MH - HeLa Cells MH - Humans MH - MCF-7 Cells MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Neoplasm Invasiveness/*pathology MH - Neoplasm Metastasis/*pathology MH - Neoplastic Processes MH - Proto-Oncogene Proteins c-mdm2/*metabolism MH - RNA, Small Interfering/metabolism MH - Receptors, Cytoplasmic and Nuclear/*metabolism MH - Transfection/methods MH - Ubiquitin/metabolism MH - Ubiquitin-Protein Ligases/metabolism MH - Ubiquitination/physiology PMC - PMC6575577 OTO - NOTNLM OT - E3 SCF-FBXO22 OT - HDM2 abundance OT - breast cancer metastasis COIS- The authors declare no conflict of interest. EDAT- 2019/05/30 06:00 MHDA- 2020/03/25 06:00 PMCR- 2019/11/28 CRDT- 2019/05/30 06:00 PHST- 2019/05/30 06:00 [pubmed] PHST- 2020/03/25 06:00 [medline] PHST- 2019/05/30 06:00 [entrez] PHST- 2019/11/28 00:00 [pmc-release] AID - 1820990116 [pii] AID - 201820990 [pii] AID - 10.1073/pnas.1820990116 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):11754-11763. doi: 10.1073/pnas.1820990116. Epub 2019 May 28.