title: BRD4 inhibitor IBET upregulates p27kip/cip protein stability in neuroendocrine tumor cells.
abstract: The prevalence of neuroendocrine tumors (NETs) has recently been increasing. Although various drugs such as Octreotide and its analogs show certain efficacy, NETs in many patients progress and metastasize. It is desirable to develop new interventions to improve the therapy. Here we show that human neuroendocrine tumor BON cells are resistant to several drugs commonly used for NET therapy, including Octreotide that activates somatostatin receptor-induced anti-proliferation, and Capecitabine and Temozolimide that damage DNA. In contrast, an inhibitor (IBET) to an epigenetic regulator, Brd4 that binds acetylated histones and upregulates transcription of multiple genes including protooncogene c-Myc, potently inhibited the NET cells. We found that IBET increased the protein levels of cyclin-dependent kinase (CDK) inhibitor p27kip/cip(or p27), but not its mRNA levels. Moreover, the p27 induction at protein level by IBET was at least partly through increasing the protein stability of p27. The increased protein stability of p27 likely resulted from IBET-mediated suppression of Skp2, an E3 ligase that can mediate p27 degradation by increasing its ubiquitinylation. These findings unravel a new mechanism whereby the IBET-induced repression of proliferation of neuroendocrine cells.
authors.affiliation: a Department of Urology , Renmin Hospital of Wuhan University , Wuhan , P.R. China.|b Abramson Family Cancer Research Institute, Department of Cancer Biology , Abramson Cancer Center, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: b Abramson Family Cancer Research Institute, Department of Cancer Biology , Abramson Cancer Center, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Matkar
authors.affiliation: c Department of Gastrointestinal Surgery , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei , P.R. China.
authors.forename: Gengchen
authors.initials: G
authors.lastname: Xie
authors.affiliation: b Abramson Family Cancer Research Institute, Department of Cancer Biology , Abramson Cancer Center, University of Pennsylvania , Philadelphia , PA , USA.|d Department of Endocrinology and Metabolism , The First Affiliated Hospital of Harbin Medical University , Harbin , P.R. China.
authors.forename: Chiying
authors.initials: C
authors.lastname: An
authors.affiliation: b Abramson Family Cancer Research Institute, Department of Cancer Biology , Abramson Cancer Center, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: b Abramson Family Cancer Research Institute, Department of Cancer Biology , Abramson Cancer Center, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Xiangchen
authors.initials: X
authors.lastname: Kong
authors.affiliation: a Department of Urology , Renmin Hospital of Wuhan University , Wuhan , P.R. China.
authors.forename: Xiuheng
authors.initials: X
authors.lastname: Liu
authors.affiliation: b Abramson Family Cancer Research Institute, Department of Cancer Biology , Abramson Cancer Center, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D000069287:Capecitabine / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use; D055550:Protein Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D000077204:Temozolomide; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001569:Benzodiazepines; D000069287:Capecitabine; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003606:Dacarbazine; D009687:Nuclear Proteins; D015282:Octreotide; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D000077204:Temozolomide; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C436291:CDKN1B protein, human; C554645:molibresib
keywords: Brd4; IBET; Skp2; neuroendocrine tumor; p27