TUSC3: functional duality of a cancer gene

Vašíčková, Kateřina; Horak, Peter; Vaňhara, Petr

doi:10.1007/s00018-017-2660-4

Cited by 25 publications

(22 citation statements)

References 70 publications

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“…In this regard, the cirRNAs ci-ankrd52, ElciEIF3j and circFoxo3 upregulate the expression of their corresponding host genes ANKRD52 [ 30 ], EIF3J [ 31 ] and Foxo 3 [ 22 ]. To assess the potential impact of the circRNAs studied herein upon the linear RNA derived from the host gene, we focused on TUSC3 circ104557 due to the well-recognized feature of its parental gene TUSC3 as a tumor suppressor gene [ 32 ]. To explore its potential activity, we transduced a TUSC3 circ104557 lentiviral expression construct and the empty vector in the colorectal cancer cell lines studied.…”

Section: Resultsmentioning

confidence: 99%

“…Of the four identified genes hosting circRNAs that undergo hypermethylation-associated downregulation, only TUSC3 had been previously reported to be epigenetically inactivated in human cancer [ 32 ]. TUSC3 epigenetic loss has been found in colorectal cancer, the same tumor type in which we initiated our screening, and it is associated with adverse prognosis [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

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Circular RNA CpG island hypermethylation-associated silencing in human cancer

et al. 2018

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Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circRNAs), a type of RNA transcripts lacking 5′-3′ ends and forming closed loops that are gaining relevance in cancer biology, are also a target of epigenetic inactivation in tumors. To tackle this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in conjuction with circRNA expression microarrays. We have found that the loss of DNA methylation provokes a release of circRNA silencing. In particular, we have identified that promoter CpG island hypermethylation of the genes TUSC3 (tumor suppressor candidate 3), POMT1 (protein O-mannosyltransferase 1), ATRNL1 (attractin-like 1) and SAMD4A (sterile alpha motif domain containing 4A) is linked to the transcriptional downregulation of both linear mRNA and the hosted circRNA. Although some circRNAs regulate the linear transcript, we did not observe changes in TUSC3 mRNA levels upon TUSC3 circ104557 overexpression. Interestingly, we found circRNA-mediated regulation of target miRNAs and an in vivo growth inhibitory effect upon TUSC3 circ104557 transduction. Data mining for 5′-end CpG island methylation of TUSC3, ATRNL1, POMT1 and SAMD4A in cancer cell lines and primary tumors showed that the epigenetic defect was commonly observed among different tumor types in association with the diminished expression of the corresponding transcript. Our findings support a role for circRNA DNA methylation-associated loss in human cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circular RNA CpG island hypermethylation-associated silencing in human cancer

et al. 2018

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“…The roles of TUSC3 in cancer progression showed context-dependent manner in several solid tumors. TUSC3 was initially identified as a homozygous deleted gene in metastasized prostate cancer patients and its deficiency upregulated cancer progression and tumorigenesis in ovarian, prostate, glioblastoma and pancreatic cancers 20 – 24 . However, it has been also reported that TUSC3 was associated with genetic amplification or enhanced cancer progression in head and neck cancer and colorectal cancer 20 , 25 , 26 .…”

Section: Introductionmentioning

confidence: 99%

“…TUSC3 was initially identified as a homozygous deleted gene in metastasized prostate cancer patients and its deficiency upregulated cancer progression and tumorigenesis in ovarian, prostate, glioblastoma and pancreatic cancers 20 – 24 . However, it has been also reported that TUSC3 was associated with genetic amplification or enhanced cancer progression in head and neck cancer and colorectal cancer 20 , 25 , 26 . In particular, the controversial observations were reported in TUSC3-dependent oncogenesis in lung cancer 27 – 30 .…”

Section: Introductionmentioning

confidence: 99%

miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

et al. 2018

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Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.

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“…Participants with two copies of the Tumor Supressor Candidate 3, TUSC3 , had a 20% increased odds of pancreatic cancer compared to individuals with germline hemizygous deletions in this gene (90% credible interval (CI) for odds ratio: 1.01 - 1.39). While the direction of this effect is inconsistent with its putative role as a tumor suppressor, up-regulation of TUSC3 and possible oncogenic roles for this gene have been reported in cancers including non-small cell lung cancer, colorectal, thyroid, and head and neck cancers [24–27]. Among non-coding regions, we found that deletions for a CNV region in 8q24 were associated with a reduced risk of pancreatic cancer (90% CI: 1.09-1.59).…”

Section: Resultsmentioning

confidence: 99%

Bayesian copy number detection and association in large-scale studies

Cristiano

McKean

Carey

et al. 2020

Preprint

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Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases. Methods The Pancreatic Cancer Case and Control ConsortiumClinical and demographic characteristics of the cases and controls in PanC4 and recruitment methods have been previously described [20]. All samples were processed using GenomeStudio (version 2011.1, Genotyping Module 1.9.4). For GC-correction, we sampled a random subset of 30,000 Illumina probes, fit LOESS with span 1/3 to the scatterplot of log 2 R ratios and probe GC content, and predicted the log 2 R ratios for the full probeset from the LOESS model. For spatial correction, we applied LOESS to the GC-corrected log 2 R ratios at SNPs with balanced allele frequencies (0.4 < BAF < 0.6) ordered by genomic position within each chromosome arm and predicted the GC-corrected log 2 R ratios for the full probeset, including SNPs with imbalanced allele frequencies. The residuals from the spatial LOESS were used in all downstream analyses with CNPBayes. CNV regions:CNV regions identified for further analysis by CNPBayes were obtained from the collection of CNVs identified from a hidden Markov model as well as known CNV regions from the 1000 Genomes Project.For the former, we fit a 5-state hidden Markov model implemented in the R package VanillaICE (version 1.40.0) using default parameter settings [35]. To obtain a high confidence call set, we removed CNVs with fewer than 10 probes, CNVs with posterior probability less than 0.9, and restricted inference to autosomal chromosomes. To assess the effect of spatial adjustment on copy number inference, we stratified the samples into deciles of median absolute deviation and autocorrelation and compared the results of the 5-state hidden Markov model fit after GC-correction to the CNVs identified after spatial correction. Concordance of CNVs identified by the hidden Markov models was defined by ≥ 50% reciprocal overlap [36]. 9 CNV regions were defined by the set of non-overlapping disjoint intervals across the pooled set of all CNVs from cases and controls. We computed the number of subjects with a CNV overlapping each disjoint interval, retaining intervals where CNVs were identified in at l...

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TUSC3: functional duality of a cancer gene

Cited by 25 publications

References 70 publications

Circular RNA CpG island hypermethylation-associated silencing in human cancer

Circular RNA CpG island hypermethylation-associated silencing in human cancer

miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

Bayesian copy number detection and association in large-scale studies

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