Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF.
The genomic organization of the CDK2 gene, which overlaps the melanocyte-specific gene SILV/PMEL17, poses an interesting regulatory challenge. We show that, despite its ubiquitous expression, CDK2 exhibits tissue-specific regulation by the essential melanocyte lineage transcription factor MITF. In addition, functional studies revealed this regulation to be critical for maintaining CDK2 kinase activity and growth of melanoma cells. Expression levels of MITF and CDK2 are tightly correlated in primary melanoma specimens and predict susceptibility to the CDK2 inhibitor roscovitine. CDK2 depletion suppressed growth and cell cycle progression in melanoma, but not other cancers, corroborating previous results. Collectively, these data indicate that CDK2 activity in melanoma is largely maintained at the transcriptional level by MITF, and unlike other malignancies, it may be a suitable drug target in melanoma.
Du
Jinyan
J
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
Widlund
Hans R
HR
Horstmann
Martin A
MA
Ramaswamy
Sridhar
S
Ross
Ken
K
Huber
Wade E
WE
Nishimura
Emi K
EK
Golub
Todd R
TR
Fisher
David E
DE
D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024721:E-Box Elements / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077546:Roscovitine; D016196:S Phase / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D051020:bcl-X Protein; D058951:gp100 Melanoma Antigen
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; C497234:MITF protein, human; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C548637:PMEL protein, human; D047428:Protein Kinase Inhibitors; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051020:bcl-X Protein; D058951:gp100 Melanoma Antigen; D000077546:Roscovitine; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases