CUL4A-DDB1-circRFWD2 E3 ligase complex mediates the ubiquitination of p27 to promote multiple myeloma proliferation

Abstract

Multiple myeloma (MM) is an incurable disease characterized by the abnormal expansion of plasma cells in the bone marrow (BM). Numerous studies have shown that BM tumor cells can influence the tumor microenvironment (TME) through communication with extracellular vesicle circular RNAs (circRNAs), a type of noncoding RNA. Our study revealed that a circular RNA, circRFWD2 (hsa_circ_0015361), is expressed by MM cells and translated into a new protein, circRFWD2_369aa. We found that elevated levels of circRFWD2_369aa in MM peripheral blood samples were closely associated with poor outcomes in MM patients. Further investigation revealed that circRFWD2 promoted the degradation of p27 through the ubiquitination pathway, leading to increased proliferation of MM cells. We also confirmed the interaction between circRFWD2 and its downstream genes DDB1 and CUL4A, indicating that circRFWD2 could form an E3 ligase complex with other genes to mediate the ubiquitination of p27. Notably, the protein translated by a circular RNA of RFWD2 can also function as an E3 ligase. Our study highlights the potential of circRFWD2 as a biomarker for MM, which may improve the sensitivity and specificity of diagnosis and efficacy analyses.