Dual promoter usage as regulatory mechanism of let-7c expression in leukemic and solid tumors

Andrea Pelosi, Silvia Careccia, Giulia Sagrestani, Simona Nanni, Isabella Manni, Valeria Schinzari, Joost H A Martens, Antonella Farsetti, Hendrik G. Stunnenberg, Maria Pia Gentileschi, Donatella Del Bufalo, Ruggero De Maria, Giulia Piaggio, Maria Giulia Rizzo

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Abstract

Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARα fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARα in an all transretinoic acid (ATRA)-sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription.

Original languageEnglish
Pages (from-to)878-889
Number of pages12
JournalMolecular Cancer Research
Volume12
Issue number6
DOIs
Publication statusPublished - 2014

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Pelosi, A., Careccia, S., Sagrestani, G., Nanni, S., Manni, I., Schinzari, V., Martens, J. H. A., Farsetti, A., Stunnenberg, H. G., Gentileschi, M. P., Del Bufalo, D., De Maria, R., Piaggio, G., & Rizzo, M. G. (2014). Dual promoter usage as regulatory mechanism of let-7c expression in leukemic and solid tumors. Molecular Cancer Research, 12(6), 878-889. https://doi.org/10.1158/1541-7786.MCR-13-0410