The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads
to stimulation of HIF-1? expression and HIF-dependent attendant pathways
#MMPMID24997364
Slominski A
; Kim TK
; Bro?yna AA
; Janjetovic Z
; Brooks DL
; Schwab LP
; Skobowiat C
; Jó?wicki W
; Seagroves TN
Arch Biochem Biophys
2014[Dec]; 563
(?): 79-93
PMID24997364
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To study the effect of melanogenesis on HIF-1? expression and attendant pathways,
we used stable human and hamster melanoma cell lines in which the amelanotic vs.
melanotic phenotypes are dependent upon the concentration of melanogenesis
precursors in the culture media. The induction of melanin pigmentation led to
significant up-regulation of HIF-1?, but not HIF-2?, protein in melanized cells
for both lines. Similar upregulation of nuclear HIF-1? was observed in excisions
of advanced melanotic vs. amelanotic melanomas. In cultured cells, melanogenesis
also significantly stimulated expression of classical HIF-1-dependent target
genes involved in angiogenesis and cellular metabolism, including glucose
metabolism and stimulation of activity of key enzymes in the glycolytic pathway.
Several other stress related genes containing putative HRE consensus sites were
also upregulated by melanogenesis, concurrently with modulation of expression of
HIF-1-independent genes encoding for steroidogenic enzymes, cytokines and growth
factors. Immunohistochemical studies using a large panel of pigmented lesions
revealed that higher levels of HIF-1? and GLUT-1 were detected in advanced
melanomas in comparison to melanocytic nevi or thin melanomas localized to the
skin. However, the effects on overall or disease free survival in melanoma
patients were modest or absent for GLUT-1 or for HIF-1?, respectively. In
conclusion, induction of the melanogenic pathway leads to robust upregulation of
HIF-1-dependent and independent pathways in cultured melanoma cells, suggesting a
key role for melanogenesis in regulation of cellular metabolism.
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