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Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins.

ABSTRACT: Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4-implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING-containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.

SUBMITTER: Gong Y

PROVIDER: S-EPMC4251771 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins.

Gong Yongxing Y Zack Travis Ian TI Morris Luc G T LG Lin Kan K Hukkelhoven Ellen E Raheja Radhika R Tan I-Li IL Turcan Sevin S Veeriah Selvaraju S Meng Shasha S Viale Agnes A Schumacher Steven E SE Palmedo Perry P Beroukhim Rameen R Chan Timothy A TA

Nature genetics 20140504 6

Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern ...[more]

PMID: 24793136

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Project description:BackgroundSuccinate dehydrogenase (SDH) loss and mastermind-like 3 (MAML3) translocation are two clinically important genetic alterations that correlate with increased rates of metastasis in subtypes of human paraganglioma and pheochromocytoma (PPGL) neuroendocrine tumors. Although hypotheses propose that succinate accumulation after SDH loss poisons dioxygenases and activates pseudohypoxia and epigenomic hypermethylation, it remains unclear whether these mechanisms account for oncogenic transcriptional patterns. Additionally, MAML3 translocation has recently been identified as a genetic alteration in PPGL, but is poorly understood. We hypothesize that a key to understanding tumorigenesis driven by these genetic alterations is identification of the transcription factors responsible for the observed oncogenic transcriptional changes.MethodsWe leverage publicly-available human tumor gene expression profiling experiments (N = 179) to reconstruct a PPGL tumor-specific transcriptional network. We subsequently use the inferred transcriptional network to perform master regulator analyses nominating transcription factors predicted to control oncogenic transcription in specific PPGL molecular subtypes. Results are validated by analysis of an independent collection of PPGL tumor specimens (N = 188). We then perform a similar master regulator analysis in SDH-loss mouse embryonic fibroblasts (MEFs) to infer aspects of SDH loss master regulator response conserved across species and tissue types.ResultsA small number of master regulator transcription factors are predicted to drive the observed subtype-specific gene expression patterns in SDH loss and MAML3 translocation-positive PPGL. Interestingly, although EPAS1 perturbation is detectible in SDH-loss and VHL-loss tumors, it is by no means the most potent factor driving observed patterns of transcriptional dysregulation. Analysis of conserved SDH-loss master regulators in human tumors and MEFs implicated ZNF423, a known modulator of retinoic acid response in neuroblastoma. Subsequent functional analysis revealed a blunted cell death response to retinoic acid in SDH-loss MEFs and blunted differentiation response in SDH-inhibited SH-SY5Y neuroblastoma cells.ConclusionsThe unbiased analyses presented here nominate specific transcription factors that are likely drivers of oncogenic transcription in PPGL tumors. This information has the potential to be exploited for targeted therapy. Additionally, the observation that SDH loss or inhibition results in blunted retinoic acid response suggests a potential developmental etiology for this tumor subtype.

Dataset Information

Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins.

Publications

Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins.

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