TRIM21-dependent ubiquitination of MCCase induced by hsa_circ_0009061 drives H3K36 crotonylation to suppress epithelial ovarian cancer progression through regulating glycolysis

Histone lysine crotonylation plays a pivotal role in gene transcription in diseases. However, the relationship between its levels and epithelial ovarian cancer (EOC) peritoneal metastasis remains unclear. Here, we report that the circular RNA hsa_circ_0009061 is crucial for 3-Methylcrotonyl-CoA carboxylase (MCCase)-mediated lysine crotonylation and glycolysis. Hsa_circ_0009061 acts as a tumor suppressor and inhibits EOC metastasis as well as glycolysis. Mechanistic analysis revealed that hsa_circ_0009061 interacts with Methylcrotonyl-CoA Carboxylase Subunit 1 (MCCC1) and Methylcrotonyl-CoA Carboxylase Subunit 2 (MCCC2) to drive the Tripartite Motif Containing 21 (TRIM21)-dependent ubiquitination-mediated degradation of MCCase, leading to an increase in the histone H3 lysine 36 crotonylation (H3K36cr) level. This change is regulated by Lysine Acetyltransferase 7 (KAT7), and the increase in H3K36cr represses the transcription of Phosphofructokinase Platelet (PFKP) to impede glycolytic flux. As a result, AAV2/8 therapy targeting hsa_circ_0009061 suppressed tumor growth in an EOC patient-derived xenograft (PDX) mouse model. Besides, sodium crotonate (NaCr), 2,5-Anhydro-D-glucitol-1,6-diphosphate and AAV2/8 therapy targeting TRIM21 influences the inhibitor effect of hsa_circ_0009061 on EOC tumor metastasis in the downstream of hsa_circ_0009061/MCCase axis. In summary, our study demonstrated that hsa_circ_0009061 suppresses EOC metastasis and glycolysis via MCCase-mediated H3K36cr and reveals a potential strategy for targeting hsa_circ_0009061/MCCase axis for EOC treatment. Mechanistic modeling of circRNA-protein sheds light on the effect of hsa_circ_0009061 on TRIM21-dependent ubiquitination of MCCase and their interactions in the context of H3K36cr-induced transcriptional program in epithelial ovarian cancer.