The Promoter-Associated Noncoding RNA pncCCND1_B Assembles a Protein–RNA Complex to Regulate Cyclin D1 Transcription in Ewing Sarcoma

Autor: Paola Frisone, Claudio Sette, Neri Mercatelli, Ramona Palombo, Maria Paola Paronetto, Marco Fidaleo
Rok vydání: 2019
Předmět:
0301 basic medicine
protein-RNA
Cancer Research
Biology
Cell Line
DEAD-box RNA Helicases
Promoter Regions
03 medical and health sciences
0302 clinical medicine
Cyclin D1
Genetic
Transcription (biology)
Ewing
hemic and lymphatic diseases
Humans
Neoplastic transformation
Fusion
neoplasms
Gene
Settore BIO/16 - ANATOMIA UMANA
Oncogene Proteins
Gene knockdown
Tumor
Proto-Oncogene Protein c-fli-1
Signal Transducing
Adaptor Proteins
Untranslated
RNA-Binding Proteins
RNA
Sarcoma
Non-coding RNA
RNA Helicase A
Neoplasm Proteins
Up-Regulation
DNA-Binding Proteins
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer research
Adaptor Proteins
Signal Transducing
Cell Line
Tumor
Oncogene Proteins
Fusion
Promoter Regions
Genetic
RNA
Untranslated
RNA-Binding Protein EWS
Sarcoma
Ewing
Zdroj: Cancer Research. 79:3570-3582
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.can-18-2403
Popis: Most Ewing sarcomas are characterized by the in-frame chromosomal translocation t(11;22) generating the EWS–FLI1 oncogene. EWS–FLI1 protein interacts with the RNA helicase DHX9 and affects transcription and processing of genes involved in neoplastic transformation, including CCND1 (the cyclin D1 gene), which contributes to cell-cycle dysregulation in cancer. In this study, we found that CCND1 expression is significantly higher in patients with Ewing sarcoma compared with other sarcomas and that the pncCCND1_B RNA, a previously uncharacterized CCND1 promoter-associated noncoding (pnc) transcript, is expressed in Ewing sarcoma cells. PncCCND1_B interacted with the RNA-binding protein Sam68 and repressed CCND1 expression. Notably, knockdown of Sam68 affected pncCCND1_B subcellular localization and cyclin D1 expression. Pharmacologic impairment of DHX9/EWS–FLI1 interaction promoted RNA-dependent association of Sam68 with DHX9 and recruitment of Sam68 to the CCND1 promoter, thus repressing it. Conversely, mitogenic stimulation of Ewing sarcoma cells with IGF1 impaired Sam68/DHX9 interaction and positively regulated CCND1 expression. These studies uncover a fine-tuned modulation of the proto-oncogene CCND1 in Ewing sarcoma cells via alternative complexes formed by DHX9 with either EWS–FLI1 or pncCCND1_B-Sam68. Significance: A pncRNA-based mechanism represses expression of CCND1 through the formation of a protein–RNA complex and provides new therapeutic opportunities for patients with Ewing sarcoma.
Databáze: OpenAIRE
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