Context-dependent modulation of the tumor suppressor programed cell death 4 (PDCD4) by argenine methylation

Programmed cell death 4 (PDCD4) is a well-characterized tumor suppressor whose loss correlates with poor patient prognosis in many cancers. Yet some patients whose tumors express PDCD4 still have poor prognosis. In this dissertation, I report the identification of protein arginine methyltransferase 5 (PRMT5) as a new PDCD4 binding partner that when coexpressed with PDCD4 in a xenograft model of breast cancer causes accelerated tumor growth, dependent on both catalytically active PRMT5 and methylcompetent PDCD4. Furthermore, analysis of two independent breast cancer data sets indicates that expression of high PDCD4 and low PRMT5 correlates with better patient outcome while expression of high PDCD4 and high PRMT5 associates with poor outcome. Together, these data suggest that arginine methylation of PDCD4 switches its function from a tumor suppressor to an oncogene. This oncogenic interaction is primarily dictated by the target residue arginine 110 and secondarily by adjacent basic residues that further enhance the binding interaction. Additionally, the interaction is sensitive to levels of the universal methyl donor, Sadenosyl- L-methionine (SAM). SAM levels were found to be increased in a panel of breast cancer cells compared to a noncancerous cells line, suggesting that SAM levels are a variable to consider with regard to the PDCD4-PRMT5 interaction. iv Additionally, I report that PDCD4 is methylated during nutrient deprivation due to stabilization of PDCD4 levels and increased activity of PRMT5. Moreover, methylation of PDCD4 promotes a higher affinity interaction with the RNA helicase eIF4A and increases cell viability during nutrient deprivation. Due to poorly formed vasculature, solid tumors often have nutrient-deprived regions where methylation of PDCD4 could occur to sustain viability of cells coexpressing PDCD4 and PRMT5. These data further support that the role of PDCD4 in cancer biology should be considered in a context-dependent manner.