title: NEDD9 regulates actin dynamics through cortactin deacetylation in an AURKA/HDAC6-dependent manner.
abstract: The prometastatic protein NEDD9 (neural precursor cell expressed, developmentally downregulated 9) is highly expressed in many cancers and is required for mesenchymal individual cell migration and progression to the invasive stage. Nevertheless, the molecular mechanisms of NEDD9-driven migration and the downstream targets effecting metastasis are not well defined. In the current study, knockdown of NEDD9 in highly metastatic tumor cells drastically reduces their migratory capacity due to disruption of actin dynamics at the leading edge. Specifically, NEDD9 deficiency leads to a decrease in the persistence and stability of lamellipodial protrusions similar to knockdown of cortactin (CTTN). Mechanistically, it was shown that NEDD9 binds to and regulates acetylation of CTTN in an Aurora A kinase (AURKA)/HDAC6-dependent manner. The knockdown of NEDD9 or AURKA results in an increase in the amount of acetylated CTTN and a decrease in the binding of CTTN to F-actin. Overexpression of the deacetylation mimicking (9KR) mutant of CTTN is sufficient to restore actin dynamics at the leading edge and migration proficiency of the tumor cells. Inhibition of AURKA and HDAC6 activity by alisertib and Tubastatin A in xenograft models of breast cancer leads to a decrease in the number of pulmonary metastases. Collectively, these findings identify CTTN as the key downstream component of NEDD9-driven migration and metastatic phenotypes.
  
  
  CONCLUSIONS
  This study provides a mechanistic platform for therapeutic interventions based on AURKA and HDAC6 inhibition for patients with metastatic breast cancer to prevent and/or eradicate metastases.
authors.affiliation: Authors' Affiliations: Mary Babb Randolph Cancer Center; Departments of 2Biochemistry, 3Pathology, and 4Neurobiology and Anatomy, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Varvara K
authors.initials: VK
authors.lastname: Kozyreva
authors.forename: Sarah L
authors.initials: SL
authors.lastname: McLaughlin
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Livengood
authors.forename: Robin A
authors.initials: RA
authors.lastname: Calkins
authors.forename: Laura C
authors.initials: LC
authors.lastname: Kelley
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rajulapati
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Ice
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Smolkin
authors.forename: Scott A
authors.initials: SA
authors.lastname: Weed
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pugacheva
mesh_terms: D000107:Acetylation; D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D051356:Cortactin / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D064593:Heterografts; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010750:Phosphoproteins / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D051356:Cortactin; D056572:Histone Deacetylase Inhibitors; C099942:NEDD9 protein, human; D010750:Phosphoproteins; C576917:AURKA protein, human; D064096:Aurora Kinase A; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases