Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model.
Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein-Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the gamma-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.
Departments of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. yustein@bcm.edu
Jason T
JT
Yustein
Yen-Chun
YC
Liu
Ping
P
Gao
Chunfa
C
Jie
Anne
A
Le
Milena
M
Vuica-Ross
Wee Joo
WJ
Chng
Charles G
CG
Eberhart
P Leif
PL
Bergsagel
Chi V
CV
Dang
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004151:Dipeptides / Q000494:pharmacology; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072101:Jagged-2 Protein; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch