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Article

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Published version

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2018-08-31

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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/155233

Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms

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https://doi.org/10.1172/JCI96520

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.

Subject

Regulació cel·lular, Càncer, Limfomes

Subject (English)

Cellular control mechanisms, Cancer, Lymphomas

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Articles publicats en revistes (Fonaments Clínics)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citation

ALBERO, Robert, et al. Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms. Journal of Clinical Investigation. 2018. Vol. 128, num. 9, pags. 4132-4147. ISSN 0021-9738. [consulted: 15 of August of 2026]. Available at: https://hdl.handle.net/2445/155233

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