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Title: Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
Author: Albero, Robert
Enjuanes, Anna
Demajo, Santiago
Castellano, Giancarlo
Pinyol, Magda
García, Noelia
Capdevila, Cristina
Clot, Guillem
Suárez-Cisneros, Helena
Shimada, Mariko
Karube, Kennosuke
López-Guerra, Mónica
Colomer Pujol, Dolors
Beà Bobet, Sílvia M.
Martín-Subero, José Ignacio
Campo Güerri, Elias
Jares Gerboles, Pedro
Keywords: Regulació cel·lular
Cellular control mechanisms
Issue Date: 31-Aug-2018
Publisher: American Society for Clinical Investigation
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.
Note: Reproducció del document publicat a:
It is part of: Journal of Clinical Investigation, 2018, vol. 128, num. 9, p. 4132-4147
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ISSN: 0021-9738
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Fonaments Clínics)

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