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.
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- Supplementary Figures and Text (3,547 KB)
Supplementary Figures 1–12 & Supplementary Tables 1–3
- Supplementary Data 1 (330 KB)
2,620 CpGs most divergent between primary and metatatic tumor cell lines.
- Supplementary Data 2 (13 KB)
CpGs located outside CpG islands most divergent between primary and metastatic tumor cell lines.
- Supplementary Data 3 (14 KB)
DNA methylation profile of the TBC1D16-45/47KD promoter CpG island according to the DNA methylation microarray values in 36 melanoma cell lines.