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

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.

SUBMITTER: Yang JS

PROVIDER: S-EPMC8707130 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ER?) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E2)-stimulated, ER?-driven transcription. FASN and ER? were both necessary for the synergistic activation of ER? transcriptional activity that occurred following co-exposure to C75 and E2: first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (>100 fold) the amount of E2 required for optimal activation of ER?-mediated transcriptional activity; second, FASN blockade synergistically increased E2-stimulated ER?-mediated transcriptional activity in ER?-negative breast cancer cells stably transfected with ER?, but not in ER?-negative parental cells. Non-genomic, E2-regulated cross-talk between the ER? and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182?780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E2-stimulated ER? transactivation. FASN inhibition suppressed E2-stimulated breast cancer cell proliferation and anchorage-independent colony formation while promoting the reduction of ER? protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E2-promoted anchorage-independent growth. The ability of FASN to regulate E2/ER? signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.

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

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