title: Natural product triptolide mediates cancer cell death by triggering CDK7-dependent degradation of RNA polymerase II.
abstract: Triptolide is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biologic properties, including anticancer properties. Among its many putative targets, this compound has been reported to bind to XPB, the largest subunit of general transcription factor TFIIH, and to cause degradation of the largest subunit Rpb1 of RNA polymerase II (RNAPII). In this study, we clarify multiple important questions concerning the significance and basis for triptolide action at this core target. Triptolide decreased Rpb1 levels in cancer cells in a manner that was correlated tightly with its cytotoxic activity. Compound exposure blocked RNAPII at promoters and decreased chromatin-bound RNAPII, both upstream and within all genes that were examined, also leading to Ser-5 hyperphosphorylation and increased ubiqutination within the Rbp1 carboxy-terminal domain. Notably, cotreatment with inhibitors of the proteasome or the cyclin-dependent kinase CDK7 inhibitors abolished the ability of triptolide to ablate Rpb1. Together, our results show that triptolide triggers a CDK7-mediated degradation of RNAPII that may offer an explanation to many of its therapeutic properties, including its robust and promising anticancer properties.
authors.affiliation: Department of Pharmacology and BioTechnology, University of Bologna, Bologna Italy.
authors.forename: Stefano Giustino
authors.initials: SG
authors.lastname: Manzo
authors.forename: Zhao-Li
authors.initials: ZL
authors.lastname: Zhou
authors.forename: Ying-Qing
authors.initials: YQ
authors.lastname: Wang
authors.forename: Jessica
authors.initials: J
authors.lastname: Marinello
authors.forename: Jin-Xue
authors.initials: JX
authors.lastname: He
authors.forename: Yuan-Chao
authors.initials: YC
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capranico
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
mesh_terms: D001483:Base Sequence; D001688:Biological Products / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D017931:DNA Primers; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation; D059748:Proteolysis; D012319:RNA Polymerase II / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D001688:Biological Products; D017931:DNA Primers; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human