Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Dana Westphal - , Department of Dermatology, University Hospital Carl Gustav Carus Dresden (Author)
  • Matthias Meinhardt - , Institute of Pathology, University Hospital Carl Gustav Carus Dresden (Author)
  • Konrad Grützmann - , Institute for Medical Informatics and Biometry, Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Dresden (Author)
  • Lisa Schöne - , Department of Dermatology, Chair of Systems Biology and Genetics, University Hospital Carl Gustav Carus Dresden (Author)
  • Julian Steininger - , University Hospital Carl Gustav Carus Dresden (Author)
  • Lena T Neuhaus - , Institute of Pathology, University Hospital Carl Gustav Carus Dresden (Author)
  • Miriam Wiegel - , Department of Dermatology, University Hospital Carl Gustav Carus Dresden (Author)
  • Daniel Schrimpf - , University Hospital Heidelberg (Author)
  • Daniela E Aust - , Institute of Pathology, University Hospital Carl Gustav Carus Dresden (Author)
  • Evelin Schröck - , Institute of Clinical Genetics, Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Dresden, Tumor and Normal Tissue Bank (TNTB), University Hospital Carl Gustav Carus Dresden (Author)
  • Gustavo B Baretton - , Institute of Pathology, University Hospital Carl Gustav Carus Dresden (Author)
  • Stefan Beissert - , Department of Dermatology, University Hospital Carl Gustav Carus Dresden (Author)
  • Tareq A Juratli - , Department of Neurosurgery, University Hospital Carl Gustav Carus Dresden (Author)
  • Gabriele G Schackert - , University Hospital Carl Gustav Carus Dresden (Author)
  • Jan Gravemeyer - , German Cancer Research Center (DKFZ) (Author)
  • Jürgen C Becker - , University Hospital Essen (Author)
  • Andreas von Deimling - , University Hospital Heidelberg (Author)
  • Christian Koelsche - , University Hospital Heidelberg (Author)
  • Barbara Klink - , University Hospital Carl Gustav Carus Dresden (Author)
  • Friedegund Meier - , University Hospital Carl Gustav Carus Dresden (Author)
  • Alexander Schulz - , Department of Dermatology, University Hospital Carl Gustav Carus Dresden (Author)
  • Michael H Muders - , University Hospital Carl Gustav Carus Dresden (Author)
  • Michael Seifert - , University Medicine (Faculty of Medicine and University Hospital) (Author)

Abstract

Despite remarkable advances in treating patients with metastatic melanoma, the management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an important mechanism for the adaptation of melanoma cells to the brain environment. In this study, the methylomes and transcriptomes of a cohort of matched melanoma metastases were evaluated by integrated omics data analysis. The identified 38 candidate genes displayed distinct promoter methylation and corresponding gene expression changes in intracranial compared with extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. In accordance with the underlying promoter methylation and gene expression changes, a significantly different protein expression was confirmed for STK10, PDXK, WDR24, CSSP1, NMB, RASL11B, phosphorylated PRKCZ, PRKCZ, and phosphorylated GRB10 in the intracranial metastases. The observed changes imply a distinct intracranial phenotype with increased protein kinase B phosphorylation and a higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of phosphorylated protein kinase B and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant alterations were identified that provide insights into the molecular mechanisms that discriminate brain metastases from other organ metastases, which could be exploited by targeting the affected signaling pathways.

Details

Original languageEnglish
Number of pages30
JournalJournal of Investigative Dermatology
Early online date27 Jan 2023
Publication statusE-pub ahead of print - 27 Jan 2023
Peer-reviewedYes

External IDs

ORCID /0000-0001-7499-5125/work/130201217
unpaywall 10.1016/j.jid.2023.01.011
Scopus 85149672475
PubMed 36716920

Keywords