FOXO4 and colonic neoplasm: This might be due to increased expression of Nrf1 and Nrf2, which are the key transcription factors that drive proteasome subunit expression and are known to be regulated by mutant RAS or its downstream effectors.48, 49 The mechanistic importance of this is supported by our observation that blockade of proteasome activity by MG132 or the FDA-approved Bortezomib is sufficient to increase FOXO3A and FOXO4 protein abundance in multiple RAS-mutant colon cancer cell lines.