Dataset Information

Somatic human ZBTB7A zinc finger mutations promote cancer progression.

ABSTRACT: We recently reported that ZBTB7A is a bona fide transcription repressor of key glycolytic genes and its downregulation in human cancer contributes to tumor metabolism. As reduced expression of ZBTB7A is found only in a subset of human cancers, we explored alternative mechanisms of its inactivation by mining human cancer genome databases. We discovered recurrent somatic mutations of ZBTB7A in multiple types of human cancers with a marked enrichment of mutations within the zinc finger domain. Functional characterization of the mutants demonstrated that mutations within the zinc finger region of ZBTB7A invariably resulted in loss of function. As a consequence, the glycolytic genes were markedly upregulated in cancer cells harboring ZBTB7A zinc finger mutation, leading to increased glycolysis and proliferation. Our study uncovers the loss-of-function mutation in ZBTB7A as a novel mechanism causing elevated glycolysis in human cancer, which carries important therapeutic implication.

SUBMITTER: Liu XS

PROVIDER: S-EPMC5817916 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Somatic human ZBTB7A zinc finger mutations promote cancer progression.

Liu X-S XS Liu Z Z Gerarduzzi C C Choi D E DE Ganapathy S S Pandolfi P P PP Yuan Z-M ZM

Oncogene 20151012 23

We recently reported that ZBTB7A is a bona fide transcription repressor of key glycolytic genes and its downregulation in human cancer contributes to tumor metabolism. As reduced expression of ZBTB7A is found only in a subset of human cancers, we explored alternative mechanisms of its inactivation by mining human cancer genome databases. We discovered recurrent somatic mutations of ZBTB7A in multiple types of human cancers with a marked enrichment of mutations within the zinc finger domain. Func ...[more]

PMID: 26455326

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Project description:Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors.

Dataset Information

Somatic human ZBTB7A zinc finger mutations promote cancer progression.

Publications

Somatic human ZBTB7A zinc finger mutations promote cancer progression.

Similar Datasets

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