TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development

Dedifferentiated liposarcoma (DDLPS) constitutes 15-20% of liposarcoma (LPS) and has high rates of local recurrence and distant metastasis. Abnormal yes-associated protein (YAP) signaling 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 for DDLPS malignant progression. The levels of TP53INP2 protein expression in tumor tissues from 79 patients with DDLPS decreased progressively. Compared with primary tumors, the recurrent tumors also showed reduced TP53INP2 expression. More importantly, low TP53INP2 expression correlates with poor prognosis. TP53INP2 gain- or loss-of-function experiments in DDLPS cell lines showed profoundly inhibitory properties towards cancer malignancy. Mechanistically, TP53INP2 mainly located in mitochondria and promoted mitophagic degradation of YAP depending on VDAC1. The WW domain in YAP and the PPXY motif in VDAC1 were required for their interaction. Taken together, these data demonstrate that TP53INP2 represses DDLPS malignant progression by inactivating YAP via a mitophagy-dependent mechanism, and that TP53INP2 expression may represent a novel prognostic biomarker for the patients with advanced DDLPS.