Epigenetic Activation of a Cryptic TBC1D16 Transcript Enhances Melanoma Progression by Targeting EGFR

Nat Med. 2015 Jul;21(7):741-50. doi: 10.1038/nm.3863. Epub 2015 Jun 1.

Abstract

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Disease Progression*
  • Epigenesis, Genetic* / drug effects
  • ErbB Receptors / metabolism*
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Immunoprecipitation
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Mice, Nude
  • Molecular Weight
  • Neoplasm Metastasis
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • Treatment Outcome
  • rab GTP-Binding Proteins / metabolism

Substances

  • GTPase-Activating Proteins
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • RNA, Small Interfering
  • TBC1D16 protein, human
  • ErbB Receptors
  • rab GTP-Binding Proteins