NGF Inhibits Human Leukemia Proliferation by Downregulating Cyclin A1 Expression through Promoting Acinus/CtBP2 Association

• Authors: Chi Bun Chan, Emory University; Xia Liu, Emory University; Sung-Wuk Jang, Emory University; Stephen I-Hong Hsu, National University of Singapore; Ifor Williams, Emory University; Sumin Kang, Emory University; Jing Chen, Emory University; Keqiang Ye, Emory University
• Journal Title: Oncogene
• Volume: Volume 28, Number 43
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B | 2009-10-29, Pages 3825-3836
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/onc.2009.236
• Subjects: Health Sciences, Pathology; Health Sciences, Oncology
• Keywords: Acinus; CtBP2; Cyclin A1; Gambogic amide; Leukemia; NGF

Abstract

Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by acinus, a nuclear speckle protein. However, the molecular mechanism of how acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds acinus, which is regulated by NGF, inhibiting its stimulatory effect on cyclin A1 but not cyclin A2 expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and acinus through triggering acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF’s suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF down-regulates cyclin A1 expression through escalating CtBP2/acinus complex formation, and gambogic amide might be useful for human leukemia treatment.