RASSF6exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells

Abstract

Brain metastasis is a major contributor to cancer mortality, yet, the genetic changes underlying the development of this capacity remain poorly understood. RASSF proteins are a family of tumor suppressors that often suffer epigenetic inactivation during tumorigenesis. However, their epigenetic status in brain metastases has not been well characterized. We have examined the promoter methylation of the classical RASSF members (RASSF1A-RASSF6) in a panel of metastatic brain tumor samples. RASSF1A and RASSF2 have been shown to undergo promoter methylation at high frequency in primary lung and breast tumors and in brain metastases. Other members exhibited little or no methylation in these tumors. In examining melanoma metastases, however, we found that RASSF6 exhibits the highest frequency of inactivation in melanoma and in melanoma brain metastases. Most melanomas are driven by an activating mutation in B-Raf. Introduction of RASSF6 into a B-Raf(V600E)-containing metastatic melanoma cell line inhibited its ability to invade through collagen and suppressed MAPK pathway activation and AKT. RASSF6 also appears to increase the association of mutant B-Raf and MST1, providing a potential mechanism by which RASSF6 is able to suppress MAPK activation. Thus, we have identified a novel potential role for RASSF6 in melanoma development. Promoter methylation leading to reduced expression of RASSF6 may play an important role in melanoma development and may contribute to brain metastases.

Prognostic importance of RASSF2 expression in patients with gastric cancer who had undergone radical gastrectomy

“…We also determined that low RASSF2 expression was associated with poor prognosis. Therefore, our results were similar to previous findings [31,32].…”

“…Gharanei [31]. Recently, in a study performed by Mezzanotte et al, the authors reported that promoter methylation leading to reduced expression of RASSF6 may play an important role in melanoma development and may contribute to brain metastases [32]. We also determined that low RASSF2 expression was associated with poor prognosis.…”

Ras signaling through RASSF proteins

“…We have found that RASSF1A appears to have little effect on MAPK signaling in mutant B-Raf driven cells but family member RASSF6 actually enhances the association of MST1 with B-Raf and suppresses the phosphorylation of ERK [55]. So B-Raf signaling may be under the influence of non-RASSF1A family members.…”

“…It exhibits a distinct expression pattern compared to other RASSF family members and is epigenetically silenced in primary cancers, although to a lesser extent than RASSF1A and NORE1A [55, 110, 169]. RASSF6 binds directly to K-Ras via its RA domain and synergizes with activated K-Ras to induce apoptosis [168].…”

The discovery of a novel, Ras-mediated NORE1A/PMLIV tumor suppressor complex.

“…A class of drugs called DNA methyltransferase inhibitors exist that inhibit promoter methylation, but they have a wide range of potential side effects, as they inhibit global DNA methylation [271]. More specific inhibitors that target single DNA methyltransferase enzymes have been developed, and I have shown that one of these, Nanaomycin A, can efficiently promote the re-expression of a RASSF protein in melanoma cells [125]. Thus, using therapies that specifically target NORE1A…”