Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms
Albero, Robert (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Enjuanes, A. (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Demajo, Santiago (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Castellano, Giancarlo (Hospital Clínic i Provincial de Barcelona)
Pinyol, Magda (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
García, Noelia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Capdevila, Cristina (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Clot, Guillem (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Suárez-Cisneros, Helena (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Shimada, Mariko (Hospital Clínic i Provincial de Barcelona)
Karube, Ken (Hospital Clínic i Provincial de Barcelona)
Lopez-Guerra, Monica (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Colomer, Dolors (Hospital Clínic i Provincial de Barcelona)
Beà, Sílvia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Martin-Subero, Jose Ignacio (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Campo, Elías (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Jares, Pedro (Institut d'Investigacions Biomèdiques August Pi i Sunyer)

Data:	2018
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad PI14/00355 Ministerio de Economía y Competitividad SAF2015-64885-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-00795
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Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	Cyclin D1 ; Transcription ; RNA Pol II ; CDK9 ; Malignant lymphoid cells ; Transcription inhibitors
Publicat a:	The journal of clinical investigation, Vol. 128 Núm. 9 (August 2018) , p. 4132-4147, ISSN 1558-8238

DOI: 10.1172/JCI96520
PMID: 29990311

Postprint 56 p, 1.2 MB

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