Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR

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.

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

“…2C). The restoration of TP53TG1 expression upon transfection in HCT-116 was also associated with a decreased invasion and migration potential of these cells, as measured by the Matrigel-based xCELLigence real-time assay (31) (Fig. 2D) and the wound-healing assay (Fig.…”

“…RNA pull-down was performed essentially as described (57). Mouse xenograft and orthotopic experiments were performed as previously described (31). Statistical analyses were done using SPSS version 17.0 (SPSS) and GraphPad Prism version 5.04.…”

A non-coding function of TYRP1 mRNA promotes melanoma growth

“…In other words, the tumour suppressor miR-16 is an upstream regulator of several downstream targets such as RAB17 and NRTN that regulate cell proliferation. The role of RAB17 in tumour growth warrants further investigations in light of the ones recently identified for RAB7a and RAB5c in melanoma 52,53 . Finally, the importance of such a cascade mechanism relies on the expression level of the sponge, the amount of the sequestered miRNA and the biological function of secondary targets 24 .…”

Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma

“…In cancer, alternative promoter utilization is of major relevance, as increasing numbers of genes (e.g., LEF1, TP53, TGFB3) are now being shown to exhibit distinct alternative promoter-associated isoforms that differentially affect malignant growth (21,118). In the current study, we identified alternative promoters in genes both known and novel to gastric cancer biology with significant clinical and translational implications.…”