title: Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2.
abstract: The Skp2 (S-phase kinase associated protein 2) oncoprotein is often highly expressed in various types of human cancers. However, the mechanistic basis of its oncogenic function, as well as the upstream regulatory pathway(s) that control Skp2 activities remains not fully understood. Recently, we reported that p300 acetylates Skp2 at two conserved lysine residues K68 and K71 within its NLS (Nuclear localization signal). This modification leads to increased Skp2 stability and cytoplasmic translocation, thus contributing to elevated Skp2 oncogenic potential. Moreover, we found that the SIRT3 tumor suppressor serves as the physiological deacetylase that antagonizes p300-mediated Skp2 acetylation. Furthermore, we showed that Skp2 governs E-cadherin ubiquitination and degradation in the cytosol. Consistent with this, we observed an inverse correlation between Skp2 and E-cadherin expression in clinical breast tumor samples. Therefore, our work elucidates a novel acetylation-dependent regulatory mechanism for Skp2 oncogenic functions.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.forename: Jiateng
authors.initials: J
authors.lastname: Zhong
authors.forename: Pengda
authors.initials: P
authors.lastname: Liu
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
mesh_terms: D000107:Acetylation; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D015820:Cadherins; D044786:S-Phase Kinase-Associated Proteins; D056566:Sirtuin 3; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C525046:Sirt3 protein, mouse; C466093:SIRT3 protein, human