Melanoma proliferation and chemoresistance controlled by the DEK oncogene.
Gain of chromosome 6p is a consistent feature of advanced melanomas. However, the identity of putative oncogene(s) associated with this amplification has remained elusive. The chromatin remodeling factor DEK is an attractive candidate as it maps to 6p (within common melanoma-amplified loci). Moreover, DEK expression is increased in metastatic melanomas, although the functional relevance of this induction remains unclear. Importantly, in other tumor types, DEK can display various tumorigenic effects in part through its ability to promote proliferation and inhibit p53-dependent apoptosis. Here, we report a generalized up-regulation of DEK protein in aggressive melanoma cells and tumors. In addition, we provide genetic and mechanistic evidence to support a key role of DEK in the maintenance of malignant phenotypes of melanoma cells. Specifically, we show that long-term DEK down-regulation by independent short hairpin RNAs resulted in premature senescence of a variety of melanoma cell lines. Short-term abrogation of DEK expression was also functionally relevant, as it attenuated the traditional resistance of melanomas to DNA-damaging agents. Unexpectedly, DEK short hairpin RNA had no effect on p53 levels or p53-dependent apoptosis. Instead, we identified a new role for DEK in the transcriptional activation of the antiapoptotic MCL-1. Other MCL-1-related factors such as BCL-2 or BCL-xL were unaffected by changes in the endogenous levels of DEK, indicating a selective effect of this gene on the apoptotic machinery of melanoma cells. These results provide support for DEK as a long sought-after oncogene mapping at chromosome 6, with novel functions in melanoma proliferation and chemoresistance.
Khodadoust
Michael S
MS
Program in Immunology, Department of Dermatology, Michigan Center for Translational Pathology, and Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5640, USA.
Verhaegen
Monique
M
Kappes
Ferdinand
F
Riveiro-Falkenbach
Erica
E
Cigudosa
Juan C
JC
Kim
David S L
DS
Chinnaiyan
Arul M
AM
Markovitz
David M
DM
Soengas
María S
MS
D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002896:Chromosomes, Human, Pair 6; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein
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