Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Cancer Res Commun. 2023 Jun 20;3(6):1067-1077. doi: 10.1158/2767-9764.CRC-23-0030. eCollection 2023 Jun.
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 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 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.
CARM1 reprograms fatty acid metabolism transcriptionally to support ovarian cancer growth by producing monounsaturated fatty acids, supporting SCD1 inhibition as a rational strategy for treating CARM1-expressing ovarian cancer.
精氨酸甲基转移酶 CARM1 在几种人类癌症中表达水平较高，在卵巢癌中也观察到这种趋势。然而，针对过度表达 CARM1 的肿瘤的治疗方法尚未得到探索。癌细胞利用代谢重编程，例如脂肪酸来生存。在这里，我们报告 CARM1 促进单不饱和脂肪酸的合成，并且脂肪酸重编程代表了表达 CARM1 的卵巢癌的代谢脆弱性。CARM1 促进编码脂肪酸代谢限速酶的基因的表达，例如乙酰辅酶 A 羧化酶 1（ACC1）和脂肪酸合酶（FASN）。此外，CARM1 上调硬脂酰辅酶 A 去饱和酶 1（SCD1），通过去饱和作用产生单不饱和脂肪酸。因此，CARM1 增强脂肪酸的合成，随后用于单不饱和脂肪酸的合成。因此，抑制 SCD1 以依赖于 CARM1 状态的方式抑制卵巢癌细胞的生长，通过添加单不饱和脂肪酸可以挽救这种抑制。一致地，表达 CARM1 的细胞对添加饱和脂肪酸更耐受。实际上，SCD1 抑制以依赖于 CARM1 的方式在原位异种移植和同基因小鼠模型中对卵巢癌表现出疗效。总之，我们的数据表明，CARM1 通过转录重编程脂肪酸代谢并通过药物抑制 SCD1 可以作为表达 CARM1 的卵巢癌的有效治疗方法。
CARM1 通过产生单不饱和脂肪酸在转录水平上重新编程脂肪酸代谢以支持卵巢癌的生长，支持通过抑制 SCD1 作为治疗表达 CARM1 的卵巢癌的合理策略。
