STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma

Oncogene. 2013 Nov 7;32(45):5283-91. doi: 10.1038/onc.2012.543. Epub 2012 Nov 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • B-Lymphocytes / metabolism*
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Heterografts
  • Humans
  • Lymphoma, B-Cell / metabolism*
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Antigen, B-Cell / metabolism

Substances

  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Receptors, Antigen, B-Cell
  • Protein-Serine-Threonine Kinases
  • STK38 protein, human