title: BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma.
abstract: Genetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies.
  
  
  
  The impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity.
  
  
  
  Sensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or bAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine.
  
  
  
  NEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.
authors.affiliation: Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA.
authors.forename: Mansi
authors.initials: M
authors.lastname: Parasramka
authors.affiliation: Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA.
authors.forename: Irene K
authors.initials: IK
authors.lastname: Yan
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA.
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Maji
authors.affiliation: Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Foye
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Asmann
authors.affiliation: Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA. patel.tushar@mayo.edu.
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D062085:RNA, Long Noncoding / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C400134:BAP1 protein, human; C577276:NEAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D043222:Ubiquitin Thiolesterase; D000093542:Gemcitabine
keywords: BAP1; Cholangiocarcinoma; Cisplatin; Combination therapy; Gemcitabine; LncRNA; NEAT-1