Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-a (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPa occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPa-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPa-p30. We show that wild-type C/EBPa and C/EBPa-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPa represses, C/EBPa-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPa in AML.

Hughes, J. M., Legnini, I., Salvatori, B., Masciarelli, S., Marchioni, M., Fazi, F., Morlando, M., Bozzoni, I., Fatica, A., C/EBPa-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia, <<ONCOTARGET>>, 2015; 6 (21): 18534-18544. [doi:10.18632/oncotarget.4069] [http://hdl.handle.net/10807/147551]

C/EBPa-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia

Masciarelli, Silvia;
2015

Abstract

Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-a (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPa occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPa-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPa-p30. We show that wild-type C/EBPa and C/EBPa-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPa represses, C/EBPa-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPa in AML.
2015
Inglese
Hughes, J. M., Legnini, I., Salvatori, B., Masciarelli, S., Marchioni, M., Fazi, F., Morlando, M., Bozzoni, I., Fatica, A., C/EBPa-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia, <<ONCOTARGET>>, 2015; 6 (21): 18534-18544. [doi:10.18632/oncotarget.4069] [http://hdl.handle.net/10807/147551]
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