title: Spectomycin B1 as a novel SUMOylation inhibitor that directly binds to SUMO E2.
abstract: Conjugation of small ubiquitin-like modifier (SUMO) to protein (SUMOylation) regulates multiple biological systems by changing the functions and fates of a large number of proteins. Consequently, abnormalities in SUMOylation have been linked to multiple diseases, including breast cancer. Using an in situ cell-based screening system, we have identified spectomycin B1 and related natural products as novel SUMOylation inhibitors. Unlike known SUMOylation inhibitors such as ginkgolic acid, spectomycin B1 directly binds to E2 (Ubc9) and selectively blocks the formation of the E2-SUMO intermediate; that is, Ubc9 is the direct target of spectomycin B1. Importantly, either spectomycin B1 treatment or Ubc9 knockdown inhibited estrogen-dependent proliferation of MCF7 human breast-cancer cells. Our findings suggest that Ubc9 inhibitors such as spectomycin B1 have potential as therapeutic agents against hormone-dependent breast cancers.
authors.affiliation: Chemical Genetics Laboratory, ‡Zhang Initiative Research Unit, §Antibiotics Laboratory, RIKEN, ∥Drug Discovery Platforms Cooperation Division, ⊥Chemical Biology Research Group, #Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Hirohama
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Isao
authors.initials: I
authors.lastname: Fukuda
authors.forename: Seiji
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Hisato
authors.initials: H
authors.lastname: Saitoh
authors.forename: Motoki
authors.initials: M
authors.lastname: Takagi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-ya
authors.forename: Kaori
authors.initials: K
authors.lastname: Honda
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Tamio
authors.initials: T
authors.lastname: Saito
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakao
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
mesh_terms: D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012459:Salicylates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015398:Signal Transduction; D000198:Spectinomycin / Q000737:chemistry / Q000494:pharmacology*; D058207:Sumoylation; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D012459:Salicylates; C112485:ginkgolic acid; D000198:Spectinomycin; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9