title: Differential expression of SUMO-specific protease 7 variants regulates epithelial-mesenchymal transition.
abstract: Two Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 7 (SENP7) variants are naturally expressed in breast epithelia. Breast cancer (BCa) onset down-regulates the short SENP7 splice variant (SENP7S) and enhances the long transcript (SENP7L). Here, we show that SENP7L induction promotes gene expression profiles that favor aberrant proliferation and initiate epithelial-mesenchymal transition (EMT). SENP7L exhibits an interaction domain for the epigenetic remodeler heterochromatin protein 1 α (HP1α) and isopeptidase activity against SUMO-modified HP1α. Loss of this interaction domain, as observed with SENP7S, favors HP1α SUMOylation. SUMOylated HP1α is enriched at E2F-responsive and mesenchymal gene promoters, silences transcription of these genes, and promotes cellular senescence. Elevated SENP7L renders HP1α hypo-SUMOylated, which relieves transcriptional repression of the same genes and concurrently decreases transcription of epithelial-promoting genes via an HP1α-independent mechanism. Consequently, SENP7L levels correlate with EMT, motility, and invasiveness of BCa cells. Stable knockdown of elevated SENP7L levels lessens the dissemination of highly metastatic BCa cells to the lungs from primary implantation sites in in vivo studies. Thus, differential splicing of the SENP7 regulates either tumor suppression or progression.
authors.affiliation: Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. tbawa@mdanderson.org
authors.forename: Tasneem
authors.initials: T
authors.lastname: Bawa-Khalfe
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Lu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zuo
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.forename: Ruhee
authors.initials: R
authors.lastname: Dere
authors.forename: Feng-Ming
authors.initials: FM
authors.lastname: Lin
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: C000715594:CBX5 protein, human; D012333:RNA, Messenger; D000090266:Chromobox Protein Homolog 5; D010450:Endopeptidases; C533959:SENP7 protein, human