BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma

Abstract

BackgroundGenetic 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.MethodsThe 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.ResultsSensitivity 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.ConclusionsNEAT-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0587-x) contains supplementary material, which is available to authorized users.

The Advancement of Long Non-Coding RNAs in Cholangiocarcinoma Development

“…Several studies reported late stage ICC was associated with BAP1 loss, suggesting the potential tumor suppressive functions of BAP1 as a chromatin modulator [71][72][73]. Recently, the negative correlation between BAP1 and lncRNA NEAT1 in CCA is reported [45]. Knockdown of BAP1 induces the upregulation of lncRNA NEAT1 in CCA cell lines.…”

“…These lncRNAs may promote proliferation, migration and invasion of CCA cells including lncRNA AFAP1-AS1, ASAP1-IT1, CCAT1, CCAT2, H19, HULC, LINC01296, ENST0000058480.1, ENST00000517758.1, MALAT1, NEAT1, PANDAR, SNHG1, Sox2ot, SPRY4-IT1, TP73-AS1 etc. [23,29,30,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. In ICC, LncRNA CPS1-IT1 and TLINC are highly expressed [33,50].…”

“…BAP1(BRCA-1 associated protein-1) is a protein coded by BRCA-1, a tumor suppressor gene in many cancers. It is a member of the ubiquitin C-terminal hydrolase superfamily that plays a critical role in chromatin remodeling [45]. Several studies reported late stage ICC was associated with BAP1 loss, suggesting the potential tumor suppressive functions of BAP1 as a chromatin modulator [71][72][73].…”

Long noncoding RNA NEAT1 correlates with higher disease risk, worse disease condition, decreased miR‐124 and miR‐125a and predicts poor recurrence‐free survival of acute ischemic stroke

“…Long noncoding RNA (lncRNA) is a group of noncoding transcripts with more than 200 nucleotides in length, and lncRNAs are known as crucial regulators of plentiful biological processes . Long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1), which is an lncRNA that is essential for the formation of paraspeckles and interacts with many intracellular regulatory factors, has been widely investigated in the cancer field . Recently, some studies have revealed that lncRNA NEAT1 is overexpressed in myocardial infarction patients and tuberculosis patients .…”

“…7,8 Long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1), which is an lncRNA that is essential for the formation of paraspeckles and interacts with many intracellular regulatory factors, has been widely investigated in the cancer field. [9][10][11] Recently, some studies have revealed that lncRNA NEAT1 is overexpressed in myocardial infarction patients and tuberculosis patients. 12,13 Furthermore, the biological roles of lncRNA NEAT1 in cardiovascular and cerebrovascular diseases have been disclosed in some experiments, such as the promotion of lncRNA NEAT1 on inflammatory response in myocardial ischemia-reperfusion injury mice models and the inhibition of lncRNA NEAT1 knockdown on atherosclerosis-correlated events in vitro.…”