The membrane protein melanoma cell adhesion molecule (MCAM) is a novel tumor marker that stimulates tumorigenesis in hepatocellular carcinoma.
Yes-associated protein (YAP) is overexpressed and has an oncogenic role in hepatocellular carcinoma (HCC). However, whether membrane protein can serve not only as a tumor marker that reflects YAP function but also as a therapeutic target that stimulates tumorigenesis in HCC remains unknown. Here we report that the membrane protein melanoma cell adhesion molecule (MCAM) was under positive regulation by YAP and was highly elevated in HCC cells. Within the MCAM promoter, we found the presence of a cAMP Response Element (CRE; -32 to -25 nt), which is conserved among species and is essential for YAP- and CREB-dependent regulation. Moreover, the interaction between CREB and YAP at the CRE site was dependent on PTPIY-WW domain interactions. However, MCAM expression was low and could not be regulated by YAP in breast and colon cancer cells because of the low levels of the acetyltransferase p300. In HCC cells, high levels of p300 facilitated the binding of YAP to the MCAM promoter, which in turn enhanced histone acetylation and polymerase II recruitment through the dissociation of the deacetylase Sirt1. These results suggest that MCAM is an HCC-specific target of YAP. In clinical serum samples, we found that the serum levels of MCAM were highly elevated in patients with HCC compared with healthy controls and with patients with cirrhosis, hepatitis, colon cancer and breast cancer. MCAM levels were shown to be a slightly better indicator than serum alpha-fetoprotein for predicting HCC. We further demonstrated that MCAM is essential for the survival and transformation of HCC. Mechanistically, MCAM induced translation initiation and the transcriptional activities of c-Jun/c-Fos. In addition, AKT activation had an essential role in the MCAM-promoted binding of eukaryotic initiation factor 4E to c-Jun/c-Fos mRNA. In conclusion, we demonstrated that MCAM may be a potential tumor marker and therapeutic target for the diagnosis and treatment of HCC.
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
J
J
Wang
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
X
X
Tang
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
W
W
Weng
School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Y
Y
Qiao
Department of Clinical Laboratory Medicine, Ruijin Hospital of Shanghai Jiaotong University, Shanghai, China.
J
J
Lin
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
W
W
Liu
Department of Science and Research, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
R
R
Liu
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
L
L
Ma
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
W
W
Yu
Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated with Shanghai TCM University, Shanghai, China.
Y
Y
Yu
Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Q
Q
Pan
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
F
F
Sun
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D051929:CD146 Antigen / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D051929:CD146 Antigen; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C497902:MCAM protein, human; C088374:YAP1 protein, human