The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

“…The expression of HERV-K has been reported in several melanoma cell lines (Buscher et al, 2006;Buscher et al, 2005;Muster et al, 2003;Serafino et al, 2009). We examined HERV-K in four melanoma cell lines (624Mel, A375, A101D, and OM431) that have constitutive activation of p-ERK and loss of wild-type p16 with corresponding hyper-phosphorylation of RB protein (Li et al, 2010a;Rotolo et al, 2005;Zhao et al, 2008).…”

“…We have demonstrated recently that expression of HERV-K correlates with ERK activation and p16 loss in human melanoma specimens, and that inhibition of MEK and CDK4, especially in combination, suppresses HERV-K expression (Li et al, 2010b), which suggests that HERV-K may mediate BRAF-MEK-ERK and p16-CDK4-RB signaling pathways in melanoma cells. It is interesting to note that the growth characteristics of melanoma cells that can be modified by HERV-K activation (e.g., changes in cell shape, loss of melanin, anchorageindependent growth) (Serafino et al, 2009) overlap with those that can be blocked by suppression of the BRAF-MEK-ERK signaling pathway, especially with simultaneous restoration of p16 or inhibition of CDK4 (Li et al, 2010a;Rotolo et al, 2005;Zhao et al, 2008). This observation, together with the knowledge that aberrations in BRAF-MEK-ERK and p16-CDK4 pathways are early events and often co-exist during melanomagenesis, and the evidence that the RAF-MEK-ERK signaling pathway is required for the completion of HIV-1 reverse transcription (Mettling et al, 2008), prompted us to hypothesize that HERV-K is regulated by BRAF-MEK-ERK and p16-CDK4 pathways.…”

“…We examined HERV-K in four melanoma cell lines (624Mel, A375, A101D, and OM431) that have constitutive activation of p-ERK and loss of wild-type p16 with corresponding hyper-phosphorylation of RB protein (Li et al, 2010a;Rotolo et al, 2005;Zhao et al, 2008). HERV-K expression is detected using a specific HERV-K ENV antibody, as described (Muster et al, 2003;Serafino et al, 2009), that recognizes a 37 Kd spliced transmembrane domain of ENV protein (Buscher et al, 2006;Buscher et al, 2005;Muster et al, 2003). HERV-K ENV protein is prominently expressed in 624Mel and A375 cells, weakly positive in A101D cells, but barely detectable in OM431 cells (Fig.…”

“…RNAi suppresses melanoma cells in vitro and in vivo (Mangeney et al, 2005;Oricchio et al, 2007;Pothlichet et al, 2006;Serafino et al, 2009). There are several potential mechanisms to explain the role of HERV-Ks in melanomagenesis.…”

“…It is conceivable that the effect may be mediated, at least partly, through HERV-K sequences that are capable of jumping around by retro-transposition leading to mutagenesis and chromosomal abnormalities (Pothlichet et al, 2006;Tchenio & Heidmann, 1991). It is possible that the observed growth promotion and anti-apoptotic effects of activated ERK and CDK4 (Li et al, 2010a;Zhao et al, 2008) can be mediated, at least in part, by HERV-K since HERV-K has been shown to directly affect melanoma cell proliferation, differentiation, and anchorage related survival (Oricchio et al, 2007;Serafino et al, 2009). Importantly, if HERV-K drives melanomagenesis downstream of the BRAF-MEK-ERK and p16/CDK4 pathways, when HERV-K is already turned on, cells may escape the inhibitory effects of therapies targeting BRAF-MEK-ERK and p16-CDK4.…”