title: ZNF668 functions as a tumor suppressor by regulating p53 stability and function in breast cancer.
abstract: Genome-wide sequencing studies in breast cancer have recently identified frequent mutations in the zinc finger protein 668 (ZNF668), the function of which is undefined. Here, we report that ZNF668 is a nucleolar protein that physically interacts with and regulates p53 and its negative regulator MDM2. Through MDM2 binding, ZNF668 regulated autoubiquitination of MDM2 and its ability to mediate p53 ubiquitination and degradation. ZNF668 deficiency also impaired DNA damage-induced stabilization of p53. RNA interference-mediated knockdown of ZNF668 was sufficient to transform normal mammary epithelial cells. ZNF668 effectively suppressed breast cancer cell proliferation in vitro and tumorigenicity in vivo. Taken together, our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability.
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Ruozhen
authors.initials: R
authors.lastname: Hu
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.forename: Hui
authors.initials: H
authors.lastname: Dai
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Breuer
authors.forename: Katherine
authors.initials: K
authors.lastname: Stemke-Hale
authors.forename: Kaiyi
authors.initials: K
authors.lastname: Li
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Shiaw-Yih
authors.initials: SY
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D016335:Zinc Fingers
chemical_list: D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C568525:ZNF668 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2