title: Kinesin family deregulation coordinated by bromodomain protein ANCCA and histone methyltransferase MLL for breast cancer cell growth, survival, and tamoxifen resistance.
abstract: Kinesins are a superfamily of motor proteins and often deregulated in different cancers. However, the mechanism of their deregulation has been poorly understood. Through examining kinesin gene family expression in estrogen receptor (ER)-positive breast cancer cells, we found that estrogen stimulation of cancer cell proliferation involves a concerted regulation of specific kinesins. Estrogen strongly induces expression of 19 kinesin genes such as Kif4A/4B, Kif5A/5B, Kif10, Kif11, Kif15, Kif18A/18B, Kif20A/20B, Kif21, Kif23, Kif24, Kif25, and KifC1, whereas suppresses the expression of seven others, including Kif1A, Kif1C, Kif7, and KifC3. Interestingly, the bromodomain protein ANCCA/ATAD2, previously shown to be an estrogen-induced chromatin regulator, plays a crucial role in the up- and downregulation of kinesins by estrogen. Its overexpression drives estrogen-independent upregulation of specific kinesins. Mechanistically, ANCCA (AAA nuclear coregulator cancer associated) mediates E2-dependent recruitment of E2F and MLL1 histone methyltransferase at kinesin gene promoters for gene activation-associated H3K4me3 methylation. Importantly, elevated levels of Kif4A, Kif15, Kif20A, and Kif23 correlate with that of ANCCA in the tumors and with poor relapse-free survival of patients with ER-positive breast cancer. Their knockdown strongly impeded proliferation and induced apoptosis of both tamoxifen-sensitive and resistant cancer cells. Together, the study reveals ANCCA as a key mediator of kinesin family deregulation in breast cancer and the crucial role of multiple kinesins in growth and survival of the tumor cells.
  
  
  CONCLUSIONS
  These findings support the development of novel inhibitors of cancer-associated kinesins and their regulator ANCCA for effective treatment of cancers including tamoxifen-resistant breast cancers.
authors.affiliation: UC Davis Cancer Center/Basic Sciences, University of California, Davis, UCDMC Research III, Room 1400B, 4645 2nd Avenue, Sacramento, CA 95817. hwzchen@ucdavis.edu.
authors.forename: June X
authors.initials: JX
authors.lastname: Zou
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Duan
authors.forename: Junjian
authors.initials: J
authors.lastname: Wang
authors.forename: Alex
authors.initials: A
authors.lastname: Sokolov
authors.forename: Jianzhen
authors.initials: J
authors.lastname: Xu
authors.forename: Christopher Z
authors.initials: CZ
authors.lastname: Chen
authors.forename: Jian Jian
authors.initials: JJ
authors.lastname: Li
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Chen
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D013629:Tamoxifen; D004958:Estradiol; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000251:Adenosine Triphosphatases; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D016547:Kinesins