TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development

Dedifferentiated liposarcoma (DDLPS) accounts for 15-20% of liposarcoma (LPS) and has high rates of local recurrence and distant metastasis. Hyperactivation of yes-associated protein (YAP) has been implicated in DDLPS development. However, the mechanisms that drive aberrant YAP signaling remain largely unknown. Here, we show that tumor protein p53 inducible nuclear protein 2 (TP53INP2) is a potential negative modulator of the malignant progression of DDLPS. The TP53INP2 protein expression level in tumor tissues from 79 patients with DDLPS decreased progressively. Compared with primary tumors, recurrent tumors also exhibited reduced TP53INP2 expression. More importantly, low TP53INP2 expression is correlated with poor prognosis. TP53INP2 gain- or loss-of-function experiments in DDLPS cell lines showed profound inhibitory effects on processes and properties linked with cancer malignancy, such as proliferation, migration, stemness and dedifferentiation. Mechanistically, TP53INP2 is located mainly in mitochondria and promotes mitophagic degradation of YAP in a VDAC1-dependent manner. The WW domain in YAP and the PPTY motif in VDAC1 are required for their interaction. Taken together, these data demonstrate that TP53INP2 represses the malignant progression of DDLPS by inactivating YAP via a mitophagy-dependent mechanism and that TP53INP2 may constitute a novel prognostic biomarker for advanced DDLPS.