Dicer1 phospho-mimetic promotes tumor progression and dissemination.
Aryal NK, Pant V, Wasylishen AR, Rimel B, Baseler L, El-Naggar AK, Mutch DG, Goodfellow PJ, Arur S, Lozano G
Cancer Res in press 03/26/2019
Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults and DICER1 syndrome patients with DICER1 germline mutations are susceptible to childhood cancers. Dicer is phosphorylated by the ERK-MAP kinase pathway and since this pathway is activated in human cancers, we asked whether phosphorylated Dicer1 contributed to tumor development. In human endometrioid cancers, we discovered that phosphorylated DICER1 is significantly associated with invasive disease. To test a direct involvement of Dicer1 phosphorylation in tumor development, we studied mice with phospho-mimetic alterations at the two conserved Serines phosphorylated by ERK and discovered that a phospho-mimetic Dicer1 drives tumor development and dissemination in two independent murine cancer models (KRas+/LA1 and p53+/-). Our findings demonstrate that Dicer1 phospho-mimetic promotes tumor development and invasion.Full Text