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CENP-A overexpression promotes distinct fates in human cells, depending on p53 status.

ABSTRACT: Tumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays, single-cell RNA-sequencing and cell trajectory analysis, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution.

SUBMITTER: Jeffery D

PROVIDER: S-EPMC7997993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Single-cell RNA-Seq to study the effects of acute and chronic CENP-A overexpression depending on p53 status

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Bulk RNA-Seq to study the effects of CENP-A overexpression, p53 status, and X- irradiation treatment in MCF-10-2A cells

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Single-cell RNA-Seq to study the effects of acute and chronic CENP-A overexpression depending on p53 status

Project description:Single-cell RNA-Seq to study the effects of acute and chronic CENP-A overexpression depending on p53 status

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CENP-A overexpression promotes aneuploidy and karyotypic heterogeneity

Project description:Centromeric localization of the evolutionarily conserved histone H3 variant, CENP-A. is essential for chromosomal stability. CENP-A overexpression (OE) causesd its mislocalization to non-centromeric regions resulting in chromosomal instability (CIN) in yeast, flies and human cells. CENP-A OE and mislocalization have been observed in cancers and correlates with poor prognosis. However, the molecular consequences of CENP-A OE on CIN and aneuploidy have not been defined. Here, we overexpressed YFP-CENP-A in a pseudodiploid DLD1 cell line and showed that CENP-A OE leads to its mislocalization and CIN due to defects in kinetochore integrity and kinetochore-microtubule attachments. CENP-A OE also leads to its mislocalization and CIN in a xenograft mouse model. Under these conditions, it contributes to aneuploidy with karyotypic heterogeneity in human cells and xenograft mouse model. In summary, our studies provide a molecular link between CENP-A OE and aneuploidy, and suggest that karyotypic heterogeneity may contribute to the aggressive phenotype of CENP-A overexpressing cancers.

2020-07-16 | GSE154460 | GEO

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[Corrigendum] FUCA1 is induced by wild-type p53 and expressed at different levels in thyroid cancers depending on p53 status.

Project description:Subsequent to the publication of the above paper, the authors noted that: 1) there was an error on Fig. 4, page 2046, in which the symbols of α-L-fucosidase 1 (FUCA 1) and fucosyltransferase 8 (FUT 8) had been mistakenly labelled the wrong way around (FUCA 1 should have been represented by the blue bars, and FUT 8 by the red), and 2) the sentence 'Average levels of FUCA1 mRNA were low in ATC s while expression levels in PTC samples were comparable or slightly higher than those present in normal thyroid tissues (Fig. 4)', page 2046, left column, 4th line from the bottom, was not appropriate to explain the result of Fig. 4. Therefore, this sentence is replaced by: 'FUCA1 RNA expression levels were found to be lower in anaplastic thyroid cancer samples (ATC s), while they were higher in papillary thyroid cancer samples (PTC s) and in normal thyroid tissues (Fig. 4)'. The corrected version of Fig. 4 is shown below, which now accurately shows how FUCA1 RNA expression levels were found to be lower in anaplastic thyroid cancer samples (ATC s), while they were higher in papillary thyroid cancer samples (PTC s) and in normal thyroid tissues. We sincerely apologize for the mistake and the inappropriate explanation in the text, and thank the reader of our article who drew this matter to our attention. Furthermore, we regret any inconvenience these chages have caused. [the original article was published in the International Journal of Oncology 50: 2043-2048, 2017; DOI: 10.3892/ijo.2017.3968].

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