p70 S6 kinase signals tristetraprolin/Dicer-mediated maturation of microRNA-145 to regulate tumor metastasis

Abstract

Ovarian cancer is a highly metastatic tumor characterized by malignant ascites spheroids, which represent one of the most important prognostic factors of poor clinical outcome. Multicellular aggregates known as spheroids (MCS) are important for anchorage-independent growth and metastasis. MCS are also an important phenomenon of cancer stem cells. However, the factors that regulate MCS formation are largely unknown. MicroRNAs (miRNA) are short non-coding RNAs that are critically involved in different oncogenic events by actively modulating mRNA and protein synthesis. Despite their clinical significance, processes regulating miRNA biogenesis remain obscure. Here, we identify N-cadherin as a key regulator of MCS formation activated in response to p70 S6 kinase (p70S6K) signaling, a downstream effector of phosphatidylinositol 3-kinase/Akt which is hyperactive in human ovarian cancer. The results also identify a new mechanism of p70S6K function that mediates microRNA (miR)-145 coregulation of key transcription factors Twist and Sox-9, thereby enhancing N-cadherin and MCS formation. p70S6K regulates miR-145 by deactivating a distinct tristetraprolin (TPP)/Dicer program. The p70S6K phosphorylates TTP, leading to inhibition of interaction between TTP and Dicer and decreased TTP activity in miR-145 processing. Silencing of p70S6K enhances the TTP/Dicer interaction and its activating in regulating miR-145. These results providea novel regulatory mechanism of p70S6K involved in the formation and spread of MCS and insights on the development of new therapeutic targets. (This work was supported by RGC grant HKU782111 and CUHK8/CRF/11R). ©2014 American Association for Cancer Research.