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TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development

Oncogene volume 44, pages 2054–2063 (2025)Cite this article

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Abstract

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.

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Fig. 1: Lower TP53INP2 expression is related with poor prognosis in DDLPS.
Fig. 2: TP53INP2 deficiency promotes the malignant progression of DDLPS.
Fig. 3: TP53INP2 promotes mitophagy in DDLPS cells.
Fig. 4: TP53INP2 inhibits YAP activation.
Fig. 5: TP53INP2 promotes YAP degradation in a mitophagy-dependent manner.
Fig. 6: VDAC1 is required for YAP degradation via TP53INP2-mediated mitophagy.

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Data availability

The RNA-seq data discussed in this publication has been deposited into the Gene Expression Omnibus (GSE263328). All study data are included in this article and Supplementary Materials.

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Acknowledgements

We thank Dianhua Chen (School of Life Sciences, Nanjing University) for technological assistance.

Funding

This work was supported by National Natural Science Foundation of China (Grant Nos. 81974504, 82230116), National Key R&D Program of China (Grant No. 2022YFC3500202), and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-C-202208).

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Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China

    Yixuan Wang, Ying Huang, Liwei Wang, Zhixiu Chen, Lin Zhou, Guoyu Li, Jiawen Yang, Qiang Xu & Yan Shen

  2. Department of Urology, Shanghai Changhai Hospital, Naval Medical University (Second Military University), Shanghai, 200433, China

    Feng Xiang & Rui Chen

  3. Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Rui Chen

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Contributions

YS and QX designed this study. XF and RC collected the clinical samples. YXW, YH, LWW, ZXC, LZ and GYL performed experiments and analysis data. JWY and RC contributed to the discussion. YXW. and YS wrote the manuscript.

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Correspondence to Rui Chen, Qiang Xu or Yan Shen.

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All experiments related to clinical specimens were conducted in accordance with the ethical standards of the Declaration of Helsinki and according to national and international guidelines and were approved by the Research Ethics Committee of Shanghai Changhai Hospital (Approval number: CHEC2019-142). Informed consent was obtained from all participants.

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Wang, Y., Huang, Y., Wang, L. et al. TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development. Oncogene 44, 2054–2063 (2025). https://doi.org/10.1038/s41388-025-03358-4

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