RASSF8 regulates progression of cutaneous melanoma through nuclear factor-κb.
Our group previously demonstrated that the RASSF1 gene has a significant tumor suppressor role in cutaneous melanoma. The RASSF8 gene is a member of the N-terminal RASSF gene family. Previously, we identified RASSF8 (HOJ1, NCBI Gene ID:11228) expression in cutaneous melanoma; however the functional role of RASSF8 in melanoma is not known. RASSF8 expression was assessed in melanoma cell lines and tumors of different AJCC stages. Results indicated that RASSF8 expression was low in metastatic melanoma lines and decreased with melanoma progression. We then explored the mechanism of RASSF8 downregulation in melanoma by assessing methylation of RASSF8 and demonstrated that methylation of RASSF8 gene promoter was higher in advanced than in early stages melanomas. Functional activity of RASSF8 in melanoma lines by knockdown and overexpression of RASSF8 demonstrated that RASSF8 expression significantly inhibited cell growth, cell migration and invasion, whereas knockdown of RASSF8 expression significantly increased cell growth, cell migration and invasion of melanoma cells by increasing expression of P65 and its downstream target IL-6. Moreover RASSF8 was found to induce apoptosis in melanoma cells by activating the P53-P21 pathway, and also in vivo studies demonstrated that inhibiting RASSF8 increases the tumorigenic properties of human melanoma xenografts. These results suggest that RASSF8 plays a significant role in suppressing the progression of cutaneous melanoma.
Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA, USA.
Jinhua
J
Wang
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
Wei
W
Hua
Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA, USA.
Sharon K
SK
Huang
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
Kun
K
Fan
Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA, USA.
Ling
L
Takeshima
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
Ying
Y
Mao
Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA, USA.
Dave S B
DS
Hoon
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; C512680:RASSF8 protein, human; C498143:RELA protein, human; C495901:TP53 protein, human; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
P53; P65; RASSF8; melanoma; methylation