Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis

Simó-Riudalbas, Laia; Offner, Sandra; Planet, Evarist; Duc, Julien; Abrami, Laurence; Dind, Sagane; Coudray, Alexandre; Coto‐Llerena, Mairene; Ercan, Caner; Piscuoglio, Salvatore; Andersen, Claus Lindbjerg; Bramsen, Jesper B.; Trono, Didier

doi:10.1038/s41467-022-32649-7

Cited by 13 publications

(14 citation statements)

References 80 publications

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“…Although several of them are located in exons and were predicted causing protein sequence changes, none of them actually result in truncated proteins ( Table 1 ). Among these GSSV-related genes, POU5F1B is a great-ape-specific novel gene caused by the retro-position of its mother copy ( OCT4 ) on chromosome 8 (a 1,412-bp INS specifically occurred in the great-ape lineage), confirming the previous report (Simó-Riudalbas et al 2022). Initially, it was thought to be a pseudogene of OCT4 with 95% sequence similarity.…”

Section: Resultssupporting

confidence: 87%

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

Zhou

Chen

et al. 2023

Preprint

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During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (including human), gibbon and macaque, we conducted comparative genome analyses, and identified 15,885 great-ape-specific structural variants (GSSVs), including 8 coding GSSVs resulting in the creation of novel proteins (e.g. ACAN and CMYA5). Functional annotations of the GSSV-related genes revealed the enrichment of genes involved development and morphogenesis, especially neurogenesis and neural network formation, suggesting the potential role of GSSVs in shaping the great-ape-shared traits. Further dissection of the brain-related GSSVs show great-ape-specific changes of enhancer activities and gene expression in the brain, involving a group of GSSV-regulated genes (such as NOL3) that potentially contribute to the altered brain development and function in great apes. The presented data highlights the evolutionary role of structural variants in the phenotypic innovations during the origin of the great lineage.

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Section: Resultssupporting

confidence: 87%

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

Zhou

Chen

et al. 2023

Preprint

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Section: Figurementioning

confidence: 99%

“…The POU5F1B retrogene is transcribed by activation of upstream transposable element-embedded regulatory sequences in several human solid tumors including colon, stomach, breast, prostate and uterus 1 . Its expression is a negative prognostic factor in colorectal 1 , gastric 2 and hepatocellular 3 malignancies and is associated with advanced histological grades of cervical cancer 4 , where the POU5F1B locus is a papillomavirus integration hotspot 5 . Supporting its role as a cancer-promoting factor, the POU5F1B protein stimulates the proliferation of colorectal 1 , gastric 2 and hepatocellular 3 carcinoma cells in vitro and increases the growth 1,2 and metastatic 1 potential of human gastrointestinal tumor cells in mouse xenotransplantation experiments.…”

Section: Figurementioning

confidence: 99%

“…Its expression is a negative prognostic factor in colorectal 1 , gastric 2 and hepatocellular 3 malignancies and is associated with advanced histological grades of cervical cancer 4 , where the POU5F1B locus is a papillomavirus integration hotspot 5 . Supporting its role as a cancer-promoting factor, the POU5F1B protein stimulates the proliferation of colorectal 1 , gastric 2 and hepatocellular 3 carcinoma cells in vitro and increases the growth 1,2 and metastatic 1 potential of human gastrointestinal tumor cells in mouse xenotransplantation experiments. While its POU5F1/OCT4 relative is a DNA-binding transcription factor concentrated in the nucleus, POU5F1B accumulates in the cytoplasm where it associates with detergent-resistant membranes (DRM) 1 .…”

Section: Figurementioning

confidence: 99%

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POU5F1Bis a human-restricted ROCK inhibitor-sensitive oncoprotein that restructures membrane nanodomains to increase cell adhesion

Simó-Riudalbas,

Offner,

Abrami

et al. 2023

Preprint

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Evolution confers new species with distinctive biological features, which can translate in purely mechanistic speciation or in novel phenotypic traits.POU5F1Barose by retrotransposition ofPOU5F1/OCT4in the last common ancestor of modern Hominoidae. Its human product is endowed with oncogenic properties, notably promoting gastrointestinal cancer growth and metastasis. Here, we reveal that the oncogenic action of POU5F1B requires ubiquitination of lysine residues found only in the human protein. This post-translational modification is essential for POU5F1B to localize to the cytoplasm and become acylated by the DHHC17 palmitoyltransferase. This leads to POU5F1B association with detergent-resistant membrane subdomains, where it triggers the accumulation of integrins and signaling molecules, and to a stimulation of cell focal adhesion. Finally, we determined that POU5F1B stability is critically dependent on ROCK, a crucial regulator of cytoskeletal dynamics and cell motility.

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“…These biomarkers are associated with the altered the phenotypes of CRC cells and play a role in the development and progression of CRC. For example, high expression of the hominid-restricted retrogene POU5F1B in tumor tissues is associated with a poor outcome of patients with CRC and promoted the cancer growth and metastasis by activating intracellular signaling events and releasing trans-acting factors ( Simo-Riudalbas et al, 2022 ). Nowadays, with the deepening of research, recently report has found autophagy proteins have prognostic value for CRC ( Hu et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of autophagy-related genes based on single-cell RNA-sequencing in colorectal cancer

et al. 2023

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Background: Colorectal cancer (CRC) is the second most common cancer in China. Autophagy plays an important role in the initiation and development of CRC. Here, we assessed the prognostic value and potential functions of autophagy-related genes (ARGs) using integrated analysis using single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) and RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA).Methods: We analyzed GEO-scRNA-seq data from GEO using various single-cell technologies, including cell clustering, and identification of differentially expressed genes (DEGs) in different cell types. Additionally, we performed gene set variation analysis (GSVA). The differentially expressed ARGs among different cell types and those between CRC and normal tissues were identified using TCGA-RNA-seq data, and the hub ARGs were screened. Finally, a prognostic model based on the hub ARGs was constructed and validated, and patients with CRC in TCGA datasets were divided into high- and low-risk groups based on their risk-score, and immune cells infiltration and drug sensitivity analyses between the two groups were performed.Results: We obtained single-cell expression profiles of 16,270 cells, and clustered them into seven types of cells. GSVA revealed that the DEGs among the seven types of cells were enriched in many signaling pathways associated with cancer development. We screened 55 differentially expressed ARGs, and identified 11 hub ARGs. Our prognostic model revealed that the 11 hub ARGs including CTSB, ITGA6, and S100A8, had a good predictive ability. Moreover, the immune cell infiltrations in CRC tissues were different between the two groups, and the hub ARGs were significantly correlated with the enrichment of immune cell infiltration. The drug sensitivity analysis revealed that the patients in the two risk groups had difference in their response to anti-cancer drugs.Conclusion: We developed a novel prognostic 11-hub ARG risk model, and these hubs may act as potential therapeutic targets for CRC.

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Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis

Cited by 13 publications

References 80 publications

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

POU5F1Bis a human-restricted ROCK inhibitor-sensitive oncoprotein that restructures membrane nanodomains to increase cell adhesion

Prognostic value of autophagy-related genes based on single-cell RNA-sequencing in colorectal cancer

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