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Fatty acid synthase (FASN) plays an important role in cancer development, providing excess lipid sources for cancer growth by participating in de novo lipogenesis. Although several inhibitors of FASN have been developed, there are many limitations to using FASN inhibitors alone as cancer therapeutics. We therefore attempted to effectively inhibit cancer cell growth by using a FASN inhibitor in combination with an inhibitor of a deubiquitinating enzyme USP14, which is known to maintain FASN protein levels in hepatocytes. However, when FASN and USP14 were inhibited together, there were no synergistic effects on cancer cell death compared to inhibition of FASN alone. Surprisingly, USP14 rather reduced the protein levels and activity of FASN in cancer cells, although it slightly inhibited the ubiquitination of FASN. Indeed, treatment of an USP14 inhibitor IU1 did not significantly affect FASN levels in cancer cells. Furthermore, from an analysis of metabolites involved in lipid metabolism, metabolite changes in IU1-treated cells were significantly different from those in cells treated with a FASN inhibitor, Fasnall. These results suggest that FASN may not be a direct substrate of USP14 in the cancer cells. Consequently, we demonstrate that USP14 regulates proliferation of the cancer cells in a fatty acid synthase-independent manner, and targeting USP14 in combination with FASN may not be a viable method for effective cancer treatment. [ABSTRACT FROM AUTHOR]