Targeting Fatty Acid Reprogramming Suppresses CARM1-expressing Ovarian Cancer
Abstract
The arginine methyltransferase CARM1 exhibits high expression levels in several human cancers, with the trend also observed in ovarian cancer. However, therapeutic approaches targeting tumors that overexpress CARM1 have not been explored. Cancer cells exploit metabolic reprogramming such as fatty acids for their survival. Here we report that CARM1 promotes monounsaturated fatty acid synthesis and fatty acid reprogramming represents a metabolic vulnerability for CARM1-expressing ovarian cancer. CARM1 promotes the expression of genes encoding rate-limiting enzymes of de novo fatty acid metabolism such as acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN). In addition, CARM1 upregulates stearoyl-CoA desaturase 1 (SCD1) that produces monounsaturated fatty acid by desaturation. Thus, CARM1 enhances de novo fatty acids synthesis which was subsequently utilized for synthesis of monounsaturated fatty acids. Consequently, inhibition of SCD1 suppresses the growth of ovarian cancer cells in a CARM1 status–dependent manner, which was rescued by the addition of monounsaturated fatty acids. Consistently, CARM1-expressing cells were more tolerant to the addition of saturated fatty acids. Indeed, SCD1 inhibition demonstrated efficacy against ovarian cancer in both orthotopic xenograft and syngeneic mouse models in a CARM1-dependent manner. In summary, our data show that CARM1 reprograms fatty acid metabolism and targeting SCD1 through pharmacological inhibition can serve as a potent therapeutic approach for CARM1-expressing ovarian cancers.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 20, 2023
- Source ID
- 10.1158/2767-9764.crc-23-0030
Entities
People
- Aaron R Goldman
- Andrew V Kossenkov
- Heng Liu
- Hsin-Yao Tang
- Jianhuang Lin
- Meenhard Herlyn
- Rugang Zhang
- Simona Lombardi
- Wei Zhou
Organizations
- Cancer Prevention and Research Institute of Texas
- Ovarian Cancer Research Alliance
- University of Bologna
- University of Texas at Austin
- Wistar Institute