ANAPC7 promotes triple-negative breast cancer progression through ANAPC2-dependent degradation of PCGF2 and activation of STAT3.

Abstract

Although dysregulation of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) and the STAT3 activation has been linked to tumorigenesis, it is unclear how ANAPC7 (a subunit of APC/C) mediates the link between STAT3 and triple-negative breast cancer (TNBC). In this study, ANAPC7 expression in fresh TNBC and adjacent normal tissues were analyzed, and the correlation of high ANAPC7 expression with clinical pathological features and prognosis in TNBC patients was further tested. Gain- and loss-of-function, xenograft tumor model, co-immunoprecipitation assay, and ubiquitination studies were employed to elucidate the role and underlying mechanisms of ANAPC7-mediated STAT3 activity in TNBC. We showed thatANAPC7 expression was significantly elevated in TNBC tissues, and high ANAPC7 expression was correlated with clinical severity in TNBC patients. Moreover, gain- and loss-of-function experiments showed that ANAPC7 facilitates malignant progression of TNBC cells, which was also verified in a xenograft tumor model. Mechanistically, ANAPC7 promotes the ubiqui-tin-proteasome degradation of tumor suppressor PCGF2 through dependence on ANAPC2, which in turn abrogates the suppression of STAT3 activity by PCGF2, finally increased STAT3 phosphorylation, along with upregulated the expression of c-Myc, N-cadherin, Vimentin and downregulation of E-cadherin. Additionally, both restoration of PCGF2 and pharmacological inhibition of STAT3 can reverse ANAPC7-induced malignant progression of TNBC. These findings revealed how ANAPC7 coordinates ubiquitin-proteasome system to activate STAT3 signaling and exert oncogenic functions, offering new avenues to improve prognosis and treatment in TNBC. Implications: Our findings provide a rationale for further investigation of the ANAPC7-PCGF2-STAT3 axis as a potential therapeutic target in TNBC.