CircKIAA1617 promotes stemness via USP14/PGRMC1-mediated autophagy and lipid metabolism reprogramming in ER-positive breast cancer.

BACKGROUND: Breast cancer (BC) is the most common neoplasm in women, and its growth mainly depends on estrogen, but the mechanism of estrogen in BC is still not fully understood. Circular RNAs (circRNAs) represent a novel type of regulatory RNA characterized by high evolutionary conservation and stability. This study aimed to investigate the roles and mechanisms of circRNAs in ER-positive BC. METHODS: CircKIAA1617 was identified through high-throughput RNA sequencing in ER-positive BC. Gain- and loss-of-function assays were performed to evaluate the functions of circKIAA1617 in ER-positive BC cells. Chromatin immunoprecipitation (ChIP) and luciferase assays verified the regulatory effects of estrogen on circKIAA1617 expression. RNA pulldown experiments, proteomic analyses, and RNA immunoprecipitation were conducted to identify the downstream targets of circKIAA1617. RESULTS: CircKIAA1617 expression was upregulated in ER-positive BC cells and tissues, indicating an unfavorable prognosis. In vitro and in vivo studies proved the circKIAA1617 increased the proliferation and stemness of ER-positive BC cells by inducing autophagy. Mechanistically, circKIAA1617 was activated by estrogen and cyclized by EIF4A3. Moreover, circKIAA1617 could act as a scaffold to enhance the interaction between the PGRMC1 and USP14 proteins, further increasing the stability of the PGRMC1 protein by decreasing its K48-linked polyubiquitination at lysine 105. In addition, autophagy activated by the circKIAA1617/USP14/PGRMC1 axis further modulated lipid metabolic reprogramming in ER-positive BC by increasing lipophagy, which accounted for the proliferation, stemness and autophagy of ER-positive BC. CONCLUSIONS: Our results revealed that circKIAA1617 promoted the proliferation and stemness of BC cells by regulating USP14/PGRMC1-mediated autophagy and lipid metabolic reprogramming and could serve as a potential diagnostic biomarker for ER-positive BC.