Thyroid cancer patients with high miR-490-3p inhibit translation of PCBP1 mRNA, whereas in patients with low miR-490-3p PCBP1 mRNA expression is high; however, the resultant protein is targeted for degradation through the proteasome. The objective of the present study was to evaluate the molecular mechanism that regulates post-translation degradation of poly r(C) binding protein (PCBP) 1 expression in thyroid cancer cells. Mass spectrometric analysis of PCBP1 immunoprecipitates from MG-132 treated TPC1 cells revealed a list of ubiquitin ligases associated with PCBP1. RNAi-mediated silencing of the candidate ubiquitin ligases revealed that knockdown of the ubiquitin ligase UBE4A stabilized PCBP1 in TPC1 cells. Concurrent overexpression of the candidate ubiquitin ligases in the normal thyroid epithelial cell line Nthy-ori 3-1 confirmed that ubiquitin conjugation factor E4 A (UBE4A) is the ubiquitin ligase that is degrading PCBP1. Coimmunoprecipitation of HA-tagged PCBP1 in TPC1 cells cotransfected with FLAG–UBE4A revealed robust polyubiquitinated smear of PCBP1, thus confirming UBE4A as the ubiquitin ligase of PCBP1. UBE4A expression mimicked PCBP1 mRNA expression in thyroid cancer patients and was inversely correlated to PCBP1 protein expression. Low UBE4A expression level was associated with a better prognosis in thyroid cancer patients. Our data reveal a post-translational regulatory mechanism of regulating PCBP1 expression in thyroid cancer cells.