Project description:To identify proteomic signatures associated with hepatocellular carcinoma driven by MYC overexpression, proteomics was performed on the LAP-tTA/tetO-MYC mouse conditional liver cancer model. Upon MYC activation, mice form liver cancer. Differential proteomics was performed in "MYC on" (MYC-HCC) mouse liver tumors versus mouse control normal liver tissue (where MYC was not overexpressed to drive tumorigenesis -- "MYC off").
Project description:We developed the c-SRC transgenic mouse in the C57BL/6 strain to address the issue of carcinogenesis in cells with high levels of Src expression. The transgene was constructed with the human c-SRC gene downstream of the mouse metallothionein promoter to create zinc inducible gene expression. In these C57BL/6 mice, Src protein was increased in a number of tissues both with and without zinc induction, but most highly in the liver.
Project description:The molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway while fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated. A genomic approach using microarray analysis was employed to identify the subsets of genes that are altered in the liver of SRC-2-/- mice.
Project description:We futher characterized genome-wide chromatin accessibility of WT and SRC-2-/- mouse liver at CT10 through DNase-Seq. In addition,chromatin accessibility was significantly reduced in SRC-2-/- mouse liver compared to WT mice at CT10. DNase-Seq was carried out in WT and SRC-2-/- mice in liver at CT10 using two doses of DNaseI.
Project description:The molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway while fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated.
Project description:We futher characterized genome-wide chromatin accessibility of WT and SRC-2-/- mouse liver at CT10 through DNase-Seq. In addition,chromatin accessibility was significantly reduced in SRC-2-/- mouse liver compared to WT mice at CT10.
Project description:Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in recent years in developed nations1,2. The MYC oncogene or its paralogs are frequently amplified or overexpressed in particularly aggressive subtypes of cancer associated with stem cell-like features and worse clinical outcomes3,4, including in liver cancer5. Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent and S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues methionine depletion. A low methionine diet, or the methylation inhibitor 5-azacytidine limited MYC-driven tumor formation, but RAS-driven liver cancer was resistant to a low methionine diet. Metabolic tracing of methionine catabolism in MYC high cells identified increased m5C methylation of genomic DNA or ribosomal RNA. We identified NOP2, an rRNA m5C-methyltransferase as a MYC target gene. Knockdown of NOP2 selectively inhibited MYC liver cancer cell proliferation and in vivo tumorigenesis. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and NOP2 may serve as a new therapeutic target in liver cancer.
Project description:Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in recent years in developed nations.1,2 The MYC oncogene or its paralogs are frequently amplified or overexpressed in particularly aggressive subtypes of cancer associated with stem cell-like features and worse clinical outcomes,3,4 including in liver cancer.5 Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent and S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues methionine depletion. A low methionine diet, or the methylation inhibitor 5-azacytidine limited MYC-driven tumor formation, but RAS-driven liver cancer was resistant to a low methionine diet. Metabolic tracing of methionine catabolism in MYC high cells identified increased m5C methylation of genomic DNA or ribosomal RNA. We found NOP2, an rRNA m5C-methyltransferase, was regulated by both MYC and methionine. RNA bisulfite seq demonstrated that methionine depletion reduced methylation levels at 28S rRNA C4099, C3438 and C3683. NOP2 knockdown decreased the methylation at C4099, and slightly affected C3438 methylation, suggesting the involvement of NOP2 in methionine dependence. Depletion of NOP2 selectively inhibited MYC liver cancer cell proliferation, tumorigenesis and in vivo tumor growth. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and NOP2 may serve as a new therapeutic target in liver cancer.