Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA [A375_polyA]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE314384 | GEO | 2026/05/15
REPOSITORIES: GEO
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Project description:Endogenous retroviral (ERV) RNA is highly expressed in cancer, although the molecular causes and consequences remain unknown. In multiple cancer types, we identified recurrent truncating mutations in ZC3H18 (Z18), a nuclear RNA surveillance component. We show that Z18 truncating (Z18trunc) mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear RNA surveillance of oncogenic ERV RNA. In zebrafish, Z18trunc accelerated melanoma onset and selectively increased ERV RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia, TCGA melanoma, and TCGA uterine cancer patient samples also expressed higher levels of ERV RNA. In engineered human melanoma cells, Z18trunc enhanced ERV RNA accumulation more than loss of one Z18 allele, indicating dominant negative activity. In human melanoma cells, Z18trunc directly bound to and stabilized ERV RNA in the cytoplasm. Expression of zebrafish and human Z18-regulated ERV RNA was sufficient to accelerate melanoma in zebrafish. Z18-regulated ERV RNA was required for Z18trunc melanocyte development in zebrafish and for human melanoma cell growth. Our work suggests that ERV RNA, the most highly expressed transposable element RNA in cancer, promotes melanoma and potentially other cancers. This work illuminates a mechanism for elevated ERV transcripts in cancer and supports that aberrant RNA accumulation is broadly oncogenic.
2026-05-15 | GSE314385 | GEO
Project description:Endogenous retroviral (ERV) RNA is highly expressed in cancer, although the molecular causes and consequences remain unknown. In multiple cancer types, we identified recurrent truncating mutations in ZC3H18 (Z18), a nuclear RNA surveillance component. We show that Z18 truncating (Z18trunc) mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear RNA surveillance of oncogenic ERV RNA. In zebrafish, Z18trunc accelerated melanoma onset and selectively increased ERV RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia, TCGA melanoma, and TCGA uterine cancer patient samples also expressed higher levels of ERV RNA. In engineered human melanoma cells, Z18trunc enhanced ERV RNA accumulation more than loss of one Z18 allele, indicating dominant negative activity. In human melanoma cells, Z18trunc directly bound to and stabilized ERV RNA in the cytoplasm. Expression of zebrafish and human Z18-regulated ERV RNA was sufficient to accelerate melanoma in zebrafish. Z18-regulated ERV RNA was required for Z18trunc melanocyte development in zebrafish and for human melanoma cell growth. Our work suggests that ERV RNA, the most highly expressed transposable element RNA in cancer, promotes melanoma and potentially other cancers. This work illuminates a mechanism for elevated ERV transcripts in cancer and supports that aberrant RNA accumulation is broadly oncogenic.
2026-05-15 | GSE314387 | GEO
Project description:ZC3H18 (Z18) is a component of multiple nuclear RNA surveillance complexes which detect and degrade aberrant nuclear RNAs. We found recurrent truncating mutations in Z18 (Z18trunc) enriched in many cancer types, and as these truncating forms lack the distal domain required for recruitment of RNA degradation machinery, we predicted that Z18’s target transcripts would be stabilized. Expression of Z18trunc expedited melanoma onset in a zebrafish melanoma model and caused a specific accumulation of endogenous retroviral (ERV) RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia also had increased ERV expression. In engineered human melanoma cells, Z18trunc caused a more severe accumulation of ERV RNA than loss of one Z18 copy, showing dominant negative activity. Z18trunc was exported to the cytoplasm and failed to recruit RNA degradation machinery, while maintaining binding to two RNA stabilizing proteins. Z18trunc bound ERV RNA via aromatic amino acids in the zinc finger domain but failed to recruit the degradation machinery, so in lieu of destruction, ERV messages were stabilized. We find that Z18 normally specifically identifies ERV messages for destruction, while Z18trunc protects ERV RNA, contributing to oncogenesis. This work demonstrates that mutations in a second nuclear RNA surveillance component are oncogenic, supporting that deficient nuclear RNA surveillance is a broad tumor suppressive mechanism. Our work provides a specific mechanism that results in elevated ERV transcripts in cancer and reveals that nuclear RNA surveillance complexes play a complementary role in suppressing ERV expression.
2026-05-15 | GSE271491 | GEO
Project description:ZC3H18 (Z18) is a component of multiple nuclear RNA surveillance complexes which detect and degrade aberrant nuclear RNAs. We found recurrent truncating mutations in Z18 (Z18trunc) enriched in many cancer types, and as these truncating forms lack the distal domain required for recruitment of RNA degradation machinery, we predicted that Z18’s target transcripts would be stabilized. Expression of Z18trunc expedited melanoma onset in a zebrafish melanoma model and caused a specific accumulation of endogenous retroviral (ERV) RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia also had increased ERV expression. In engineered human melanoma cells, Z18trunc caused a more severe accumulation of ERV RNA than loss of one Z18 copy, showing dominant negative activity. Z18trunc was exported to the cytoplasm and failed to recruit RNA degradation machinery, while maintaining binding to two RNA stabilizing proteins. Z18trunc bound ERV RNA via aromatic amino acids in the zinc finger domain but failed to recruit the degradation machinery, so in lieu of destruction, ERV messages were stabilized. We find that Z18 normally specifically identifies ERV messages for destruction, while Z18trunc protects ERV RNA, contributing to oncogenesis. This work demonstrates that mutations in a second nuclear RNA surveillance component are oncogenic, supporting that deficient nuclear RNA surveillance is a broad tumor suppressive mechanism. Our work provides a specific mechanism that results in elevated ERV transcripts in cancer and reveals that nuclear RNA surveillance complexes play a complementary role in suppressing ERV expression.
2026-05-15 | GSE271490 | GEO
Project description:ZC3H18 (Z18) is a component of multiple nuclear RNA surveillance complexes which detect and degrade aberrant nuclear RNAs. We found recurrent truncating mutations in Z18 (Z18trunc) enriched in many cancer types, and as these truncating forms lack the distal domain required for recruitment of RNA degradation machinery, we predicted that Z18’s target transcripts would be stabilized. Expression of Z18trunc expedited melanoma onset in a zebrafish melanoma model and caused a specific accumulation of endogenous retroviral (ERV) RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia also had increased ERV expression. In engineered human melanoma cells, Z18trunc caused a more severe accumulation of ERV RNA than loss of one Z18 copy, showing dominant negative activity. Z18trunc was exported to the cytoplasm and failed to recruit RNA degradation machinery, while maintaining binding to two RNA stabilizing proteins. Z18trunc bound ERV RNA via aromatic amino acids in the zinc finger domain but failed to recruit the degradation machinery, so in lieu of destruction, ERV messages were stabilized. We find that Z18 normally specifically identifies ERV messages for destruction, while Z18trunc protects ERV RNA, contributing to oncogenesis. This work demonstrates that mutations in a second nuclear RNA surveillance component are oncogenic, supporting that deficient nuclear RNA surveillance is a broad tumor suppressive mechanism. Our work provides a specific mechanism that results in elevated ERV transcripts in cancer and reveals that nuclear RNA surveillance complexes play a complementary role in suppressing ERV expression.
2026-05-15 | GSE271489 | GEO
Project description:ZC3H18 (Z18) is a component of multiple nuclear RNA surveillance complexes which detect and degrade aberrant nuclear RNAs. We found recurrent truncating mutations in Z18 (Z18trunc) enriched in many cancer types, and as these truncating forms lack the distal domain required for recruitment of RNA degradation machinery, we predicted that Z18’s target transcripts would be stabilized. Expression of Z18trunc expedited melanoma onset in a zebrafish melanoma model and caused a specific accumulation of endogenous retroviral (ERV) RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia also had increased ERV expression. In engineered human melanoma cells, Z18trunc caused a more severe accumulation of ERV RNA than loss of one Z18 copy, showing dominant negative activity. Z18trunc was exported to the cytoplasm and failed to recruit RNA degradation machinery, while maintaining binding to two RNA stabilizing proteins. Z18trunc bound ERV RNA via aromatic amino acids in the zinc finger domain but failed to recruit the degradation machinery, so in lieu of destruction, ERV messages were stabilized. We find that Z18 normally specifically identifies ERV messages for destruction, while Z18trunc protects ERV RNA, contributing to oncogenesis. This work demonstrates that mutations in a second nuclear RNA surveillance component are oncogenic, supporting that deficient nuclear RNA surveillance is a broad tumor suppressive mechanism. Our work provides a specific mechanism that results in elevated ERV transcripts in cancer and reveals that nuclear RNA surveillance complexes play a complementary role in suppressing ERV expression.
2026-05-15 | GSE271488 | GEO
Project description:While immune checkpoint blockade (ICB) therapy has significantly improved the outcome of metastatic melanoma and non-small cell lung cancer (NSCLC), most patients do not derive long-term benefits. Previous studies suggest that treatment failure is partly due to insufficient immune recognition of tumor antigens (TAs). Notably, immune targeting of TAs has focused on TAs derived from non-synonymous genomic mutations. We used a proteogenomic approach combining RNA-sequencing and mass spectrometry to study the MHC I-immunopeptidome of cutaneous melanoma and NSCLC samples. The RNA-sequencing of each sample was used to construct sample-specific databases for the mass spectrometry-based identification of MHC I-associated peptides (MAPs). MAPs were then filtered based on their RNA expression in the respective cancer types from The Cancer Genome Atlas (TCGA-SKCM for melanoma MAPs, or TCGA-LUSC and TCGA-LUAD for NSCLC MAPs) vs. benign tissues (from the Genotype-Tissue Expression (GTEx) Project, medullary thymic epithelial cells, purified blood and bone marrow cells, and normal melanocytes for melanoma or bronchial brushing samples for NSCLC). MAPs were classified as mutated tumor-specific antigens (mTSAs, derived from non-synonymous mutations expressed in the sample of origin), or unmutated tumor antigens: aberrantly expressed tumor-specific antigens (aeTSAs, no/low expression in benign tissues and at least two times higher expression in TCGA), tumor-associated antigens (TAAs, significant expression in benign tissues and at least two times higher expression in TCGA), lineage-associated antigens (LSAs, specific expression to cancer and normal tissue of origin, i.e., lung and bronchial brushing samples for NSCLC or skin and melanocytes for melanoma). The tumor antigens described here represent attractive targets for immunotherapy of melanoma and NSCLC.
2025-02-19 | PXD043057 | Pride
Project description:While immune checkpoint blockade (ICB) therapy has significantly improved the outcome of metastatic melanoma and non-small cell lung cancer (NSCLC), most patients do not derive long-term benefits. Previous studies suggest that treatment failure is partly due to insufficient immune recognition of tumor antigens (TAs). Notably, immune targeting of TAs has focused on TAs derived from non-synonymous genomic mutations. We used a proteogenomic approach combining RNA-sequencing and mass spectrometry to study the MHC I-immunopeptidome of cutaneous melanoma and NSCLC samples. The RNA-sequencing of each sample was used to construct sample-specific databases for the mass spectrometry-based identification of MHC I-associated peptides (MAPs). MAPs were then filtered based on their RNA expression in the respective cancer types from The Cancer Genome Atlas (TCGA-SKCM for melanoma MAPs, or TCGA-LUSC and TCGA-LUAD for NSCLC MAPs) vs. benign tissues (from the Genotype-Tissue Expression (GTEx) Project, medullary thymic epithelial cells, purified blood and bone marrow cells, and normal melanocytes for melanoma or bronchial brushing samples for NSCLC). MAPs were classified as mutated tumor-specific antigens (mTSAs, derived from non-synonymous mutations expressed in the sample of origin), or unmutated tumor antigens: aberrantly expressed tumor-specific antigens (aeTSAs, no/low expression in benign tissues and at least two times higher expression in TCGA), tumor-associated antigens (TAAs, significant expression in benign tissues and at least two times higher expression in TCGA), lineage-associated antigens (LSAs, specific expression to cancer and normal tissue of origin, i.e., lung and bronchial brushing samples for NSCLC or skin and melanocytes for melanoma). The tumor antigens described here represent attractive targets for immunotherapy of melanoma and NSCLC.
2025-02-19 | PXD043059 | Pride
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2025-02-07 | GSE230489 | GEO
Project description:The “cancerized field” concept posits that cells of a given tissue share a potentially oncogenic mutation or insult and are thus cancer-prone, yet only discreet clones within the field initiate tumor formation. In melanoma, tumors frequently (~50%) carry the oncogenic BRAFV600E mutation that is also nearly always present in benign nevi that rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors and is then specifically re-expressed in melanoma tumors. Here, we show by live imaging transgenic zebrafish crestin reporters that single melanocytes in a cancerized field with oncogenic BRAFV600E and p53 tumor suppressor loss undergo a change that recapitulates the neural crest progenitor (NCP) state, and patches of these cells initiate early melanoma. The crestin element is regulated by the NCP transcription factor sox10. Forced sox10 overexpression in melanocytes accelerated melanoma formation, consistent with reprogramming to the NCP state and activation of super-enhancers that lead to melanoma. Our work highlights the importance of the reemergence of the NCP state as a barrier to melanoma initiation.
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