The H3K27me3 demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila.
Trimethylated lysine 27 of histone H3 (H3K27me3) is an epigenetic mark for gene silencing and can be demethylated by the JmjC domain of UTX. Excessive H3K27me3 levels can cause tumorigenesis, but little is known about the mechanisms leading to those cancers. Mutants of the Drosophila H3K27me3 demethylase dUTX display some characteristics of Trithorax group mutants and have increased H3K27me3 levels in vivo. Surprisingly, dUTX mutations also affect H3K4me1 levels in a JmjC-independent manner. We show that a disruption of the JmjC domain of dUTX results in a growth advantage for mutant cells over adjacent wild-type tissue due to increased proliferation. The growth advantage of dUTX mutant tissue is caused, at least in part, by increased Notch activity, demonstrating that dUTX is a Notch antagonist. Furthermore, the inactivation of Retinoblastoma (Rbf in Drosophila) contributes to the growth advantage of dUTX mutant tissue. The excessive activation of Notch in dUTX mutant cells leads to tumor-like growth in an Rbf-dependent manner. In summary, these data suggest that dUTX is a suppressor of Notch- and Rbf-dependent tumors in Drosophila melanogaster and may provide a model for UTX-dependent tumorigenesis in humans.
Herz
Hans-Martin
HM
M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, Graduate Program in Genes and Development, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030, USA.
Madden
Laurence D
LD
Chen
Zhihong
Z
Bolduc
Clare
C
Buff
Eugene
E
Gupta
Ravi
R
Davuluri
Ramana
R
Shilatifard
Ali
A
Hariharan
Iswar K
IK
Bergmann
Andreas
A
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008239:Lysine / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology / Q000502:physiology; D010858:Pigmentation / Q000235:genetics; D034622:RNA Interference; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins
D033942:Adaptor Proteins, Vesicular Transport; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497759:N protein, Drosophila; C410303:RB protein, Drosophila; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; D010089:Oxidoreductases, N-Demethylating; C527283:UTX protein, Drosophila; D008239:Lysine