title: Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells.
abstract: Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone, and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α1 (MATα1) have lower PHB1 expression, and we reported that c-MYC interacts directly with both proteins. Furthermore, c-MYC and MATα1 exert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1, and c-MYC and PHB1's role in liver tumorigenesis. We found that PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1 expression correlates inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c-MYC, MAFG, and c-MAF. Both PHB1 and MATα1 heterodimerize with MAX, bind to the E-box element, and repress E-box promoter activity. PHB1 promoter contains a repressive E-box element and is occupied mainly by MAX, MNT, and MATα1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c-MYC, c-MAF, and MAFG in cancer cells and human HCC/CCA. All 8-month-old liver-specific Phb1 knockout mice developed HCC, and one developed CCA. Five-month-old Phb1 heterozygotes, but not Phb1 flox mice, developed aberrant bile duct proliferation; and one developed CCA 3.5 months after left and median bile duct ligation. Phb1 heterozygotes had a more profound fall in the expression of glutathione synthetic enzymes and higher hepatic oxidative stress following left and median bile duct ligation.
  
  
  
  We have identified that PHB1, down-regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E-box and positively regulates MAT1A while suppressing c-MYC, MAFG, and c-MAF expression; in mice, reduced PHB1 expression predisposes to the development of cholestasis-induced CCA. (Hepatology 2017;65:1249-1266).
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.|Department of Geriatrics, Guangzhou First People's Hospital, Guangzhou, China.|State Key Laboratory of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Heping
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Jiaohong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Tony W H
authors.initials: TW
authors.lastname: Li
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Mavila
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.|Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yuanyuan
authors.identifier: 0000-0003-3956-5685
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: JinWon
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.|Institute of Pharmacy & Pharmacology, University of South China, Hengyang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Tu
authors.affiliation: Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Alagappan
authors.initials: A
authors.lastname: Annamalai
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.|Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Mazen
authors.initials: M
authors.lastname: Noureddin
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D001707:Biopsy, Needle; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D024721:E-Box Elements / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction / Q000379:methods; D000091402:Prohibitins; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: C000717328:PHB protein, human; D000091402:Prohibitins; D012333:RNA, Messenger; D012097:Repressor Proteins