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Triple‐negative breast cancer (TNBC) is fast‐growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3β) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3β inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p‐PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3β phosphorylation at high levels. Furthermore, p‐PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non‐phosphorylated GSK3β. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3β inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target., PPP1R14C is upregulated in TNBC, and promotes tumorigenesis and metastasis.PPP1R14C inhibits GSK3β by retaining its Ser9 phosphorylation and inducing its protein degradation.PPP1R14C is phosphorylated and activated by PRKCI.Inhibition of PPP1R14C phosphorylation represents a promising therapeutic strategy against TNBC

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone‐metastasis remain largely unknown. In the current study, HCC‐secreted lectin galactoside‐binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone‐metastasis‐free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal‐related events by forming a bone pre‐metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219‐meidated α‐catenin degradation prompts YAP1/β‐catenin complex‐dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC‐secreted LGALS3 in pre‐metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone‐metastasis., Hepatocellular carcinoma (HCC)‐secreted LGALS3 induces osteolytic bone metastasis (BM) via promoting osteoclast fusion and podosome formation. Mechanistically, RNF219‐mediated α‐catenin degradation results in YAP1/β‐catenin‐dependent epigenetic modifications on LGALS3 promoter, eliciting in LGALS3 upregulation in HCC. Blocking YAP1/β‐catenin complex formation on LGALS3 promoter via verteporfin reduces LGALS3 expression and effectively inhibits HCC bone‐metastasis (HCC‐BM), which represents a potential strategy for HCC‐BM clinical treatment.