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Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms
Robert Albero, … , Elías Campo, Pedro Jares
Robert Albero, … , Elías Campo, Pedro Jares
Published July 10, 2018
Citation Information: J Clin Invest. 2018;128(9):4132-4147. https://doi.org/10.1172/JCI96520.
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Research Article Cell biology

Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms

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Abstract

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1–dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1–overexpressing tumors.

Authors

Robert Albero, Anna Enjuanes, Santiago Demajo, Giancarlo Castellano, Magda Pinyol, Noelia García, Cristina Capdevila, Guillem Clot, Helena Suárez-Cisneros, Mariko Shimada, Kennosuke Karube, Mónica López-Guerra, Dolors Colomer, Sílvia Beà, José Ignacio Martin-Subero, Elías Campo, Pedro Jares

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Figure 1

Cyclin D1 binds genome-wide in MCL cell lines.

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Cyclin D1 binds genome-wide in MCL cell lines.
(A) Venn diagram represen...
(A) Venn diagram representing cyclin D1 ChIP-Seq peaks in 4 MCL cell lines. (B) Distribution of cyclin D1–interacting regions over specific genomic regions in MCL cell lines. Box plots showing cyclin D1 tag density of the different genomic regions and pie charts displaying the genomic distribution of genomic intervals, with a number of tags higher than the mean. The distribution across the human genome is represented as a control. (C) Venn diagram representing cyclin D1–targeted genes identified by ChIP-Seq in MCL cell lines. Genes were considered targets when they displayed cyclin D1–binding sites located within 1 kb upstream of their TSS. (D) Average signal profile of cyclin D1 around the TSS (±3 kb) in MCL cell lines. (E) Top hits of the functional annotation clustering analysis of common cyclin D1 target genes among the 4 MCL cell lines. Only the genes with the most significant peaks in their promoters (–log P > 350) were considered for the analysis. (F) Genome browser view of the ChIP-Seq tag density plots of 4 representative cyclin D1 target genes. (G) ChIP-qPCR validation of 8 selected cyclin D1 target genes in GRANTA-519. The fold change enrichments relative to a negative region are presented (mean ± SEM) (n = 2).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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