Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

Abstract

The majority of clinical deaths among patients with triple-negative breast cancer (TNBC) are caused by uncontrolled cell proliferation and aggressive metastases, which is regulated by hyperactive glycogen synthase kinase 3 beta (GSK3β); however, the underlying mechanisms remain largely unknown. In the present study, we found that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) was specifically upregulated in TNBC, compared with that in normal tissues and non-TNBC. High PPP1R14C expression correlated significantly with shorter 5-year relapse-free survival and overall survival in patients with TNBC. Overexpressing PPP1R14C promoted, while suppression of PPP1R14C decreased the cell proliferation and the aggressive phenotype of TNBC cells, in vitro and in vivo. Importantly, we revealed that PPP1R14C interacted with and inactivated type 1 Ser/Thr protein phosphatase (PP1) to sustain GSK3β phosphorylation at S9, and induced the ubiquitylation and degradation of non-phosphorylated GSK3β (S9A) via recruiting E3 ligase, TRIM25. Furthermore, treating with C2 ceramide (C2), which recovered kinase activity of GSK3β, resulted in tumor growth inhibition in PPP1R14C-overexpressing TNBC cells. Our findings reveal a novel mechanism whereby PPP1R14C sustains inactive GSK3β, which might lead to targeted therapy for TNBC.