USP14 Regulates Cancer Cell Growth in a Fatty Acid Synthase-Independent Manner.

Ji Su Yang,Mingyu Kong,Byung Hwa Jung,Jinyoung Park,Naeun Yoon,Hyunbeom Lee

doi:10.3390/ijms222413437

Abstract

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.

Highlights

Fatty acid synthase (FASN) is an essential enzyme in de novo lipogenesis that catalyzes the synthesis of palmitate, a 16-carbon chain saturated fatty acid (FA), from acetyl-CoA and malonyl-CoA in the presence of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) [1,2,3,4]
Since Usp14 regulates the level of FASN in mouse primary hepatocytes (MPHs), we predicted that knockdown or inhibition of FASN and USP14 together would have a synergistic effect in reducing the proliferation of cancer cells
FASN has been a therapeutic target for cancer for a few decades, FASN blockade has yet to be successful in clinical settings

Summary

Introduction

Fatty acid synthase (FASN) is an essential enzyme in de novo lipogenesis that catalyzes the synthesis of palmitate, a 16-carbon chain saturated fatty acid (FA), from acetyl-CoA and malonyl-CoA in the presence of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) [1,2,3,4]. Tumor cells require more lipid sources for cancer growth and survival, which is highly dependent on de novo lipogenesis through FASN [5,6]. Many studies have shown that inhibition of FASN activity by pharmacological drugs and siRNAs induces apoptosis of cancer cells in vitro [11]. Various FASN inhibitors were developed as anticancer drugs, but most of them failed in clinical trials with the exception of TVB-2640, which is currently undergoing phase 2 clinical trials in combination with other drugs for HER2+ breast cancer [12,13]. Most FASN inhibitors have unexpected toxicities in vivo that may be attributed to a lack of target selectivity, pharmacological side effects, and metabolic flexibility of cancer cells [14,15,16,17,18,19]. When the FASN activity is inhibited solely using a FASN inhibitor, compensatory adaptive responses including an increase in the expression of FASN itself are likely to occur, resulting in mitigated efficacy of the FASN inhibitor in vivo [4,11]

Methods

Results

Conclusion