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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 3

Cyclin D1 binding correlates with gene expression levels.

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Cyclin D1 binding correlates with gene expression levels.
(A) Distributi...
(A) Distribution of genes showing cyclin D1 peaks within their promoters (5 kb upstream of the TSS) according to their respective gene expression levels. All genes were sorted into 50 equal bins based on their expression levels. Results are shown as mean ± SEM of all 4 MCL cell lines. (B) Linear correlation between cyclin D1 binding and transcription. Genes were sorted as in A. The average of cyclin D1 ChIP-Seq normalized tag densities at promoters and the RPKM-normalized expression levels are shown for each bin. Spearman’s correlation, ρ = 0.98, P < 2.2 × 10–16. (C) Profile of cyclin D1 occupancy around the TSS in Z-138 cells. Genes were divided into 10 groups based on their expression levels (from higher to lower expression). The distribution of the cyclin D1 ChIP-Seq tag density average around the TSS (±1 kb) is displayed for each group. (D) Linear correlation between cyclin D1 binding in MCL cell lines and gene expression in MCL primary samples (n = 122). Genes were sorted into 50 equal bins based on their expression in MCL samples. For each bin, the cyclin D1 ChIP-Seq tag density average in the MCL cell lines and the gene expression mean in primary samples are shown. Spearman’s correlation, ρ = 0.97, P < 2.2 × 10–16. (E) Heatmap showing the cyclin D1 ChIP-Seq tag density within gene promoters of JVM13-cD1T286A and MCL cell lines. Each row represents a gene centered on the TSS (±5 kb). Promoters are sorted by the number of cyclin D1 tags in Z-138 cells. (F) Linear correlation between cyclin D1 binding and gene expression in JVM13-cD1T286A cells. Genes were sorted into 50 equal bins as in B. Spearman’s correlation, ρ = 0.97, P < 2.2 × 10–16.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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