title: STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma.
abstract: The MYC protooncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. Besides constituting a formidable therapeutic target, MYC also has an essential function in normal physiology, thus creating the need for context-specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B-cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC-addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, whereas its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC-addicted tumors in vivo, thus providing a novel viable target for treating these malignancies.
authors.affiliation: Joint Centers for Systems Biology, Columbia University, New York, NY, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Bisikirska
authors.forename: S J
authors.initials: SJ
authors.lastname: Adam
authors.forename: M J
authors.initials: MJ
authors.lastname: Alvarez
authors.forename: P
authors.initials: P
authors.lastname: Rajbhandari
authors.forename: R
authors.initials: R
authors.lastname: Cox
authors.forename: C
authors.initials: C
authors.lastname: Lefebvre
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.forename: G E
authors.initials: GE
authors.lastname: Rieckhof
authors.forename: D W
authors.initials: DW
authors.lastname: Felsher
authors.forename: A
authors.initials: A
authors.lastname: Califano
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human