Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo

Chromosomal instability is a hallmark of cancer, but also an instigator of aneuploidy-induced stress, reducing cellular fitness. To better understand how cells with CIN adjust to aneuploidy and adopt a malignant fate in vivo, we performed a genome-wide mutagenesis screen in mice. We find that specifically aneuploid tumors inactivate Stat1 signaling in combination with increased Myc activity. By contrast, loss of p53 is common, but not enriched in CIN tumors. Validation in another tissue type confirmed that CIN promotes immune cell infiltration, which is alleviated by Stat1 loss combined with Myc activation, but not with p53 inactivation, or Myc activation alone. Importantly, we find that this mechanism is preserved in human aneuploid cancers. We conclude that aneuploid cancers inactivate Stat1 signaling to circumvent immune surveillance.

ORP4L is a prerequisite for the induction of T-cell leukemogenesis associated with human T-cell leukemia virus 1

Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. Here we report that ORP4L is expressed in ATL cells but not normal T-cells. ORP4L ablation completely blocks T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice while engineering ORP4L expression in T-cells results in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L for the initiation of T-cell leukemogenesis. For molecular insight, loss of miR-31 caused by HTLV-1 induces ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation, NF-κB-dependent p53 inactivation induced pro-oncogenes expression and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cells deterioration by HTLV-1 that can be therapeutically targeted.

Systems approaches identify the consequences of monosomy in somatic human cells

Chromosome loss that results in monosomy is detrimental to viability, yet it is frequently observed in cancers. How cancers survive with monosomy is unknown. Using p53-deficient monosomic cell lines, we find that chromosome loss impairs proliferation and genomic stability. Transcriptome and proteome analysis demonstrates reduced expression of genes encoded on the monosomes, which is partially compensated in some cases. Monosomy also induces global changes in gene expression. Pathway enrichment analysis reveals that genes involved in ribosome biogenesis and translation are downregulated in all monosomic cells analyzed. Consistently, monosomies display defects in protein synthesis and ribosome assembly. We further show that monosomies are incompatible with p53 expression, likely due to defects in ribosome biogenesis. Accordingly, impaired ribosome biogenesis and p53 inactivation are associated with monosomy in cancer. Our systematic study of monosomy in human cells explains why monosomy is so detrimental and reveals the importance of p53 for monosomy occurrence in cancer.

The Role of K-Ras and P53 in Biliary Tract Carcinoma

Objective: Biliary tract cancers are among the most fatal subtypes of gastrointestinal cancer. The pathogenesis of these tumors involves several molecular alterations in the genes. This review article focuses mainly on the role of K-Ras (a proto-oncogene) and p53 (a tumor-suppressor gene) which are among the most commonly mutated genes, with K-Ras activation being detected in 50% to 75% and P53 inactivation in 30% to 40% of biliary tract carcinomas. Methods: PubMed and Google Scholar were searched using the terms TP53, KRAS, mutation, biliary tract carcinoma, cholangiocarcinoma, murine model. In total, 72 articles were reviewed of which 26 articles from the 21st Century were included in this review. The articles excluded were mere repetitions, duplicates or were irrelevant. No data was retrieved from posters, presentations, cell lines and symposiums. Moreover, experiments involving bile aspirations were not included in this review article. Results: Three studies conducted in China, Japan and Taiwan reported a positive correlation between K-Ras mutation and biliary tract carcinoma. Only one study conducted in China showed the sole correlation between p53 inactivation and biliary tract carcinoma. Among the studies conducted in China, Japan and Europe, only four showed a positive association between both K-Ras mutation and p53 inactivation and biliary tract carcinoma. Conclusion: K-Ras and p53 mutation both contribute to biliary tract carcinoma. K-Ras mutation, however, has a much higher frequency as compared to p53 inactivation in these cancers. Keywords: p53, K-Ras, mutation, biliary tract carcinoma, cholangiocarcinoma, murine models. Continuous..

Cancer cells escape p53’s tumor suppression through ablation of ZDHHC1-mediated p53 palmitoylation

The inactivation of tumor-suppressor genes contributes heavily to oncogenesis. The mutation of TP53 has been well-studied and recognized as a major factor in the development of tumors. Yet other means of p53 inactivation has not been well-elucidated. We previously identified a hypermethylated gene ZDHHC1 that suppresses tumor growth when the expression was restored, but the specific mechanism was yet to be found. The protein product of ZDHHC1 is an S-palmitoyltransferase and we have identified p53 as a substrate for ZDHHC1-mediated palmitoylation, specifically at the C135, C176, and C275 residues. The novel form of post-translational modification of p53 is required for the nuclear translocation of the tumor suppressor. p53 recruited DNMT3A to ZDHHC1 promoter and is responsible for the hypermethylation of ZDHHC1. The epigenetic feedback loop formed by ZDHHC1 and p53 sheds light on the inactivation of p53 without the presence of genetic mutations.