suz12 inactivation in p53- and nf1-deficient zebrafish accelerates the onset of malignant peripheral nerve sheath tumors and expands the spectrum of tumor types.

Abstract

Polycomb repressive complex 2 (PRC2) is an epigenetic regulator of gene expression that possesses histone methyltransferase activity. PRC2 trimethylates lysine 27 of histone H3 proteins (H3K27me3) as a chromatin modification associated with repressed transcription of genes frequently involved in cell proliferation or self-renewal. Loss-of-function mutations in the PRC2 core subunit SUZ12 have been identified in a variety of tumors, including malignant peripheral nerve sheath tumors (MPNSTs). To determine the consequences of SUZ12 loss in the pathogenesis of MPNST and other cancers, we used CRISPR-Cas9 to disrupt the open reading frame of each of two orthologous suz12 genes in zebrafish: suz12a and suz12b We generated these knockout alleles in the germline of our previously described p53 (also known as tp53)- and nf1-deficient zebrafish model of MPNSTs. Loss of suz12 significantly accelerated the onset and increased the penetrance of MPNSTs compared to that in control zebrafish. Moreover, in suz12-deficient zebrafish, we detected additional types of tumors besides MPNSTs, including leukemia with histological characteristics of lymphoid malignancies, soft tissue sarcoma and pancreatic adenocarcinoma, which were not detected in p53/nf1-deficient control fish, and are also contained in the human spectrum of SUZ12-deficient malignancies identified in the AACR Genie database. The suz12-knockout tumors displayed reduced or abolished H3K27me3 epigenetic marks and upregulation of gene sets reported to be targeted by PRC2. Thus, these zebrafish lines with inactivation of suz12 in combination with loss of p53/nf1 provide a model of human MPNSTs and multiple other tumor types, which will be useful for mechanistic studies of molecular pathogenesis and targeted therapy with small molecule inhibitors.

• Authors: Felix Oppel, Dong H Ki, Mark W Zimmerman, Kenneth N Ross, Ting Tao, Hui Shi, Shuning He, Jon C Aster, A Thomas Look
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 13 Issue 8 (08 27 2020) ISSN: 1754-8411 [Electronic] England
• PMID: 32651197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. Published by The Company of Biologists Ltd.

Chemical References

• Antineoplastic Agents
• Neurofibromin 1
• Protein Kinase Inhibitors
• Tumor Suppressor Protein p53
• Zebrafish Proteins
• tp53 protein, zebrafish
• MAP Kinase Kinase Kinases

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Animals
• Animals, Genetically Modified
• Antineoplastic Agents (pharmacology)
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• DNA Methylation
• Disease Models, Animal
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Leukemia (genetics, metabolism, pathology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• Neurofibromin 1 (deficiency, genetics)
• Neurofibrosarcoma (drug therapy, genetics, metabolism, pathology)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Sarcoma (genetics, metabolism, pathology)
• Signal Transduction
• Soft Tissue Neoplasms (genetics, metabolism, pathology)
• Tumor Suppressor Protein p53 (deficiency, genetics)
• Zebrafish (genetics, metabolism)
• Zebrafish Proteins (deficiency, genetics)