Rad6 is a Potential Early Marker of Melanoma Development.
Melanoma is the leading cause of death from skin cancer in industrialized countries. Several melanoma-related biomarkers and signaling pathways have been identified; however, their relevance to melanoma development/progression or to clinical outcome remains to be established. Aberrant activation of Wnt/β-catenin pathway is implicated in various cancers including melanoma. We have previously demonstrated Rad6, an ubiquitin-conjugating enzyme, as an important mediator of β-catenin stability in breast cancer cells. Similar to breast cancer, β-catenin-activating mutations are rare in melanomas, and since β-catenin signaling is implicated in melanoma, we examined the relationship between β-catenin levels/activity and expression of β-catenin transcriptional targets Rad6 and microphthalmia-associated transcription factor-M (Mitf-M) in melanoma cell models, and expression of Rad6, β-catenin, and Melan-A in nevi and cutaneous melanoma tissue specimens. Our data show that Rad6 is only weakly expressed in normal human melanocytes but is overexpressed in melanoma lines. Unlike Mitf-M, Rad6 overexpression in melanoma lines is positively associated with high molecular weight β-catenin protein levels and β-catenin transcriptional activity. Double-immunofluorescence staining of Rad6 and Melan-A in melanoma tissue microarray showed that histological diagnosis of melanoma is significantly associated with Rad6/Melan-A dual positivity in the melanoma group compared to the nevi group (P=.0029). In contrast to strong β-catenin expression in normal and tumor areas of superficial spreading malignant melanoma (SSMM), Rad6 expression is undetectable in normal areas and Rad6 expression increases coincide with increased Melan-A in the transformed regions of SSMM. These data suggest a role for Rad6 in melanoma pathogenesis and that Rad6 expression status may serve as an early marker for melanoma development.
Department of Dermatology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Center for Molecular Medicine and Genetics, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201. Electronic address: krosner@med.wayne.edu.
Karli
K
Rosner
Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201.
Shreelekha
S
Adsule
Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201.
Brittany
B
Haynes
Department of Dermatology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201.
Evangelia
E
Kirou
Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201.
Ikuko
I
Kato
Department of Dermatology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201.
Darius R
DR
Mehregan
Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Pathology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201. Electronic address: shekharm@karmanos.org.
Malathy P V
MP
Shekhar