Mesothelioma is a fatal cancer of the mesothelial lining that is caused by asbestos exposure. The most common forms of mesothelioma arise in the pleural and peritoneal cavities of the lung and abdomen. Current treatment involves surgical resection and chemotherapy, but this approach is marginally successful and leads to drug resistant disease. We study sulforaphane (SFN), a nature derived anti-cancer agent that has high bioavailability and low toxicity. Our goal is to identify sulforaphane responsive targets in mesothelioma. Protein arginine methyltransferase 5 (PRMT5) is an epigenetic modifier that acts with methylosome protein 50 (MEP50) to symmetrically dimethylate arginine residues on histones H3 and H4 to silence target gene expression. PRMT5/MEP50 histone methylation has been implicated in cancer and is associated with silencing of tumor suppressors leading to enhanced cancer development. Our studies show that PRMT5/MEP50 knockdown reduces H4R3me2s and attenuates the cancer phenotype. Moreover, SFN reduces PRMT5/MEP50 function and cancer cell proliferation, spheroid formation, invasion and migration. Further, forced expression of PRMT5/MEP50 antagonizes SFN suppression of the cancer phenotype, suggesting that loss of PRMT5/MEP50 is required for SFN action. SFN suppression of mesothelioma tumor formation is associated with reduced PRMT5/MEP50 levels and activity. These findings suggest that SFN treatment suppresses PRMT5/MEP50 activity to attenuate the cancer phenotype. We also examined SFN impact on AKT/mTOR and MEK/ERK1/2 signaling which act together to activate translation of selected mRNA species via regulation of the eIF4F complex. AKT/mTOR activity leads to 4E-BP1 phosphorylation, leading to the release of eIF4E, which binds to eIF4G to assemble the eIF4F complex. MEK/ERK1/2 signaling activates MNK1/2 which activates eIF4E in the eIF4F complex. These events result in a selective increase in the translation of a subset of mRNAs. We show that SFN treatment suppresses AKT/mTOR activity leading to reduced phosphorylation of 4E-BP1 which would be expected to reduce assembly of the eIF4F complex. However, we also observe an unexpected increase in MEK/ERK1/2 activity and MNK1/2 phosphorylation which we propose is a compensatory response to the inhibition of activity of the eIF4F complex. These findings suggest that SFN may suppress eIF4E-dependent translation to attenuate the mesothelioma cancer phenotype.