ABSTRACT
Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.
Subject(s)
Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Non-alcoholic Fatty Liver Disease/pathology , Obesity/pathology , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Carcinoma, Hepatocellular/metabolism , Diet, High-Fat , Disease Models, Animal , Hepatocytes/metabolism , Humans , Liver/metabolism , Liver/pathology , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Neoplasms/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/metabolism , Obesity/metabolism , Oxidative Stress , Protein Tyrosine Phosphatase, Non-Receptor Type 2/deficiency , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism , Signal TransductionABSTRACT
The emergence of whole-genome annotation approaches is paving the way for the comprehensive annotation of the human genome across diverse cell and tissue types exposed to various environmental conditions. This has already unmasked the positions of thousands of functional cis-regulatory elements integral to transcriptional regulation, such as enhancers, promoters, and anchors of chromatin interactions that populate the noncoding genome. Recent studies have shown that cis-regulatory elements are commonly the targets of genetic and epigenetic alterations associated with aberrant gene expression in cancer. Here, we review these findings to showcase the contribution of the noncoding genome and its alteration in the development and progression of cancer. We also highlight the opportunities to translate the biological characterization of genetic and epigenetic alterations in the noncoding cancer genome into novel approaches to treat or monitor disease. SIGNIFICANCE: The majority of genetic and epigenetic alterations accumulate in the noncoding genome throughout oncogenesis. Discriminating driver from passenger events is a challenge that holds great promise to improve our understanding of the etiology of different cancer types. Advancing our understanding of the noncoding cancer genome may thus identify new therapeutic opportunities and accelerate our capacity to find improved biomarkers to monitor various stages of cancer development. Cancer Discov; 6(11); 1215-29. ©2016 AACR.
Subject(s)
DNA Methylation/genetics , Genome, Human , Neoplasms/genetics , Chromatin/genetics , Enhancer Elements, Genetic , Epigenomics , Gene Expression Regulation, Neoplastic , Genetic Therapy , Humans , Neoplasms/pathology , Promoter Regions, GeneticABSTRACT
Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.
Subject(s)
Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Mutation , Polymorphism, Single Nucleotide , CRISPR-Cas Systems , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Regulatory Sequences, Nucleic Acid , Transcription Factors/metabolismABSTRACT
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
