MicroRNA29a regulates the expression of the nuclear oncogene Ski

Abstract

MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate growth and differentiation. miRNAs are frequently located at cancer-specific fragile sites in the human genome, such as chromosome 7q. The nuclear oncogene SKI is up-regulated in acute myeloid leukemia (AML) with −7/del7q. Here we asked whether loss of miRNAs on chromosome 7q may explain this up-regulation. miR-29a expression was found to be down-regulated in AML with −7/del7q. Forced expression of miR-29a down-regulated Ski and its target gene, Nr-CAM, whereas miR-29a inhibition induced Ski expression. Luciferase assays validated a functional binding site for miR-29a in the 3′ untranslated region of SKI. Finally, in samples of AML patients, we observed an inverse correlation of Ski and miR-29a expression, respectively. In conclusion, up-regulation of Ski in AML with −7/del7q is caused by loss of miR-29a. miR-29a may therefore function as an important tumor suppressor in AML by restraining expression of the SKI oncogene.

The GATA1s isoform is normally down-regulated during terminal haematopoietic differentiation and over-expression leads to failure to repress MYB, CCND2 and SKI during erythroid differentiation of K562 cells

“…It has been shown to block erythroid differentiation by a direct interaction with GATA1 involving the C-terminal Zinc finger [28]. SKI is an important component of the histone deacetylase complex, and over-expression of SKI has been implicated in the pathogenesis of acute myeloid leukaemia [29-31]. These observations suggest that a GATA1s-SKI interaction may be important for the maintenance of an expanded MEP compartment with a block to terminal differentiation as seen in transient abnormal myelopoiesis.…”

miRNAs in acute myeloid leukemia

“…Akt2 was also identified to be a target of the three miR-29 members that was significantly increased in the AML blasts. In myeloid leukemogenesis, overexpressed c-Myc inhibits miR-29 family expression, resulting in increased Akt2 and CCND2 protein expression in AML [20, 22-24]. …”

Making a long story short: noncoding RNAs and chromosome change

“…A direct role for MIR29A, an miRNA found at the fragile site in 7q32.3, as a tumor suppressor is demonstrated in that there is a functional binding site for MIR29A in the 3¢UTR of SKI and overexpression of MIR29A reduces the expression of the SKI oncogene (Teichler et al, 2011). This chromosome fragile site (7q32.3) also coincides with FLJ43663, a presumed ncRNA.…”

“…In another example, upregulation of the oncogene SKI in acute myeloid leukemia patients has been demonstrated to be resultant from loss of miRNAs on chromosome 7q (whole chromosome or long arm of 7 deletions) (Teichler et al, 2011). A direct role for MIR29A, an miRNA found at the fragile site in 7q32.3, as a tumor suppressor is demonstrated in that there is a functional binding site for MIR29A in the 3¢UTR of SKI and overexpression of MIR29A reduces the expression of the SKI oncogene (Teichler et al, 2011).…”