title: Dual promoter usage as regulatory mechanism of let-7c expression in leukemic and solid tumors.
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.
  
  
  CONCLUSIONS
  Alternative promoter usage represents a regulatory mechanism of let-7c expression in different tissues. Mol Cancer Res; 12(6); 878-89. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis;
authors.forename: Andrea
authors.initials: A
authors.lastname: Pelosi
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis;
authors.forename: Silvia
authors.initials: S
authors.lastname: Careccia
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis;
authors.forename: Giulia
authors.initials: G
authors.lastname: Sagrestani
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis; Medical Pathology Institute, Catholic University;
authors.forename: Simona
authors.initials: S
authors.lastname: Nanni
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis;
authors.forename: Isabella
authors.initials: I
authors.lastname: Manni
authors.affiliation: Department of Internal Medicine, Sapienza University of Rome; Laboratory of Gene Expression, Fondazione Andrea Cesalpino;
authors.forename: Valeria
authors.initials: V
authors.lastname: Schinzari
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis; Institute of Cell Biology and Neurobiology, National Research Council (CNR), Rome, Italy; and.
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis;
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Gentileschi
authors.affiliation: Department of Experimental Oncology, Laboratory of Experimental Chemotherapy, Regina Elena National Cancer Institute;
authors.forename: Donatella
authors.initials: D
authors.lastname: Del Bufalo
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis;
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis;
authors.forename: Giulia
authors.initials: G
authors.lastname: Piaggio
authors.affiliation: Authors' Affiliations: Department of Experimental Oncology, Laboratory of Molecular Oncogenesis; rizzo@ifo.it.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Rizzo
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D057890:Epigenomics; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007438:Introns; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D006657:Histones; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D014212:Tretinoin