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Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer.
Gastroenterology. 2017 06; 152(8):2037-2051.e22.G

Abstract

BACKGROUND & AIMS

Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice.

METHODS

We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves. We analyzed changes in expression of these signature genes, at mRNA and protein levels, after small interfering RNA-mediated silencing of YAP in Sk-Hep1, SNU182, HepG2, or pancreatic cancer cells, as well as incubation with thiostrepton (an inhibitor of forkhead box M1 [FOXM1]) or verteporfin (inhibitor of the interaction between YAP and TEA domain transcription factor 4 [TEAD4]). We performed co-immunoprecipitation and chromatin immunoprecipitation experiments. We collected liver tissues from mice that express a constitutively active form of YAP (YAPS127A) and analyzed gene expression signatures and histomorphologic parameters associated with chromosomal instability. Mice were given injections of thiostrepton and livers were collected and analyzed by immunoblotting, immunohistochemistry, histology, and real-time polymerase chain reaction. We performed immunohistochemical analyses on tissue microarrays of 105 HCCs and 7 nontumor liver tissues.

RESULTS

Gene expression patterns associated with chromosome instability, called CIN25 and CIN70, were detected in HCCs from patients with shorter survival time or early cancer recurrence. TEAD4 and YAP were required for CIN25 and CIN70 signature expression via induction and binding of FOXM1. Disrupting the interaction between YAP and TEAD4 with verteporfin, or inhibiting FOXM1 with thiostrepton, reduced the chromosome instability gene expression patterns. Hyperplastic livers and tumors from YAPS127A mice had increased CIN25 and CIN70 gene expression patterns, aneuploidy, and defects in mitosis. Injection of YAPS127A mice with thiostrepton reduced liver overgrowth and signs of chromosomal instability. In human HCC tissues, high levels of nuclear YAP correlated with increased chromosome instability gene expression patterns and aneuploidy.

CONCLUSIONS

By analyzing cell lines, genetically modified mice, and HCC tissues, we found that YAP cooperates with FOXM1 to contribute to chromosome instability. Agents that disrupt this pathway might be developed as treatments for liver cancer. Transcriptome data are available in the Gene Expression Omnibus public database (accession numbers: GSE32597 and GSE73396).

Authors+Show Affiliations

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.International Educational-Scientific Center, Ashgabat City, Turkmenistan.Medical Faculty Mannheim, Medical Research Center, University of Heidelberg, Mannheim, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.Medical Faculty Mannheim, Medical Research Center, University of Heidelberg, Mannheim, Germany.Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: kai.breuhahn@med.uni-heidelberg.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28249813

Citation

Weiler, Sofia M E., et al. "Induction of Chromosome Instability By Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer." Gastroenterology, vol. 152, no. 8, 2017, pp. 2037-2051.e22.
Weiler SME, Pinna F, Wolf T, et al. Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer. Gastroenterology. 2017;152(8):2037-2051.e22.
Weiler, S. M. E., Pinna, F., Wolf, T., Lutz, T., Geldiyev, A., Sticht, C., Knaub, M., Thomann, S., Bissinger, M., Wan, S., Rössler, S., Becker, D., Gretz, N., Lang, H., Bergmann, F., Ustiyan, V., Kalin, T. V., Singer, S., Lee, J. S., ... Breuhahn, K. (2017). Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer. Gastroenterology, 152(8), 2037-e22. https://doi.org/10.1053/j.gastro.2017.02.018
Weiler SME, et al. Induction of Chromosome Instability By Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer. Gastroenterology. 2017;152(8):2037-2051.e22. PubMed PMID: 28249813.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer. AU - Weiler,Sofia M E, AU - Pinna,Federico, AU - Wolf,Thomas, AU - Lutz,Teresa, AU - Geldiyev,Aman, AU - Sticht,Carsten, AU - Knaub,Maria, AU - Thomann,Stefan, AU - Bissinger,Michaela, AU - Wan,Shan, AU - Rössler,Stephanie, AU - Becker,Diana, AU - Gretz,Norbert, AU - Lang,Hauke, AU - Bergmann,Frank, AU - Ustiyan,Vladimir, AU - Kalin,Tatiana V, AU - Singer,Stephan, AU - Lee,Ju-Seog, AU - Marquardt,Jens U, AU - Schirmacher,Peter, AU - Kalinichenko,Vladimir V, AU - Breuhahn,Kai, Y1 - 2017/02/27/ PY - 2016/10/27/received PY - 2017/02/07/revised PY - 2017/02/19/accepted PY - 2017/3/3/pubmed PY - 2017/8/15/medline PY - 2017/3/3/entrez KW - CIN KW - Cell Division KW - Signal Transduction KW - Tumorigenesis SP - 2037 EP - 2051.e22 JF - Gastroenterology JO - Gastroenterology VL - 152 IS - 8 N2 - BACKGROUND & AIMS: Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. METHODS: We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves. We analyzed changes in expression of these signature genes, at mRNA and protein levels, after small interfering RNA-mediated silencing of YAP in Sk-Hep1, SNU182, HepG2, or pancreatic cancer cells, as well as incubation with thiostrepton (an inhibitor of forkhead box M1 [FOXM1]) or verteporfin (inhibitor of the interaction between YAP and TEA domain transcription factor 4 [TEAD4]). We performed co-immunoprecipitation and chromatin immunoprecipitation experiments. We collected liver tissues from mice that express a constitutively active form of YAP (YAPS127A) and analyzed gene expression signatures and histomorphologic parameters associated with chromosomal instability. Mice were given injections of thiostrepton and livers were collected and analyzed by immunoblotting, immunohistochemistry, histology, and real-time polymerase chain reaction. We performed immunohistochemical analyses on tissue microarrays of 105 HCCs and 7 nontumor liver tissues. RESULTS: Gene expression patterns associated with chromosome instability, called CIN25 and CIN70, were detected in HCCs from patients with shorter survival time or early cancer recurrence. TEAD4 and YAP were required for CIN25 and CIN70 signature expression via induction and binding of FOXM1. Disrupting the interaction between YAP and TEAD4 with verteporfin, or inhibiting FOXM1 with thiostrepton, reduced the chromosome instability gene expression patterns. Hyperplastic livers and tumors from YAPS127A mice had increased CIN25 and CIN70 gene expression patterns, aneuploidy, and defects in mitosis. Injection of YAPS127A mice with thiostrepton reduced liver overgrowth and signs of chromosomal instability. In human HCC tissues, high levels of nuclear YAP correlated with increased chromosome instability gene expression patterns and aneuploidy. CONCLUSIONS: By analyzing cell lines, genetically modified mice, and HCC tissues, we found that YAP cooperates with FOXM1 to contribute to chromosome instability. Agents that disrupt this pathway might be developed as treatments for liver cancer. Transcriptome data are available in the Gene Expression Omnibus public database (accession numbers: GSE32597 and GSE73396). SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/28249813/Induction_of_Chromosome_Instability_by_Activation_of_Yes_Associated_Protein_and_Forkhead_Box_M1_in_Liver_Cancer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(17)30182-8 DB - PRIME DP - Unbound Medicine ER -