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Targeting SLP2-mediated lipid metabolism reprograming restricts proliferation and metastasis of hepatocellular carcinoma and promotes sensitivity to Lenvatinib

Abstract

SLP2, a protein located on mitochondrial, has been shown to be associated with mitochondrial biosynthesis. Here we explored the potential mechanisms by which SLP2 regulates the development of hepatocellular carcinoma. SLP2 could bind to the c-terminal of JNK2 to affect the ubiquitinated proteasomal degradation pathway of JNK2 and maintain the protein stability of JNK2. The increase of JNK2 markedly increases SREBP1 activity, promoting SREBP1 translocation into the nucleus to promote de novo lipogenesis. Alteration of the JNK2 C-terminal disables SLP2 from mediating SLP2-enhanced de novo lipogenesis. YTHDF1 interacts with SLP2 mRNA in a METTL3/m6A-dependent manner. In a spontaneous HCC animal model, SLP2/c-Myc/sgP53 increases the incidence rate of spontaneous HCC, tumor volume, and tumor number. Importantly, statistical analyses show that levels of SLP2 correlate with tumor sizes, tumor metastasis, overall survival, and disease-free survival of the patients. Targeting the SLP2/SREBP1 pathway effectively inhibits proliferation and metastasis of HCC tumors with high SLP2 expression in vivo combined with lenvatinib. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic SLP2, providing a mechanistic link between de novo lipogenesis and HCC.

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Fig. 1: SLP2 is frequently upregulated in HCC and is a promising prognostic biomarker for HCC.
Fig. 2: SLP2 enhances HCC cell proliferation, migration, and invasion in vivo and in vitro.
Fig. 3: SLP2 could affect tumor progression through lipid metabolism.
Fig. 4: SLP2 could interact with the C-terminus of JNK2.
Fig. 5: SLP2 could maintain the protein stability of JNK2 and regulate SREBP1-mediated lipid metabolism through JNK2.
Fig. 6: SLP2 and JNK2 together promote the translocation of mature SREBP1 to the nucleus.
Fig. 7: Expression of SLP2 is regulated by METTL3 and YTHDF1.
Fig. 8: Targeting the SLP2/SREBP1 pathway effectively inhibits proliferation and metastasis of HCC tumors with high SLP2 expression in vivo.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. The relevant mRNA databases can be found at the following sites. https://doi.org/10.6084/m9.figshare.20087705.

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Acknowledgements

We thank Qingsong Hu for his valuable daily discussions. We thank OEbiotech company for the technical support of RNAseq and mass spectrometry analysis.

Funding

This study was supported by the National Key R&D Program of China (grant no. 2019YFA0709300 and 2019YFC1605001), the National Natural Science Foundation of China (grant no. 81772588, U19A2008, 81972307, 82103219, 82102705, and 81773194), China Postdoctoral Science Foundation (2020M671911, 2020TQ0313, 2020M682023), and the Natural Science Foundation of Anhui Province (2008085QH376). Youth Innovation Key Fund Project of USTC (WK9110000153-2020,YD9100002003-2019).

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YL: formal analysis, investigation, methodology, writing – original draft. LS: investigation, data curation. HG: methodology, validation. SZ: investigation. WC: methodology, visualization. CJ: formal analysis, software. FM: methodology, validation. SL: methodology. BZ: data curation. YY: data curation. KM: validation, XL: validation, TC: validation; XG: formal analysis; NZ: formal analysis; JW: supervision; YL: writing– review & editing, methodology; LL: funding acquisition, conceptualization.

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Correspondence to Jiabei Wang, Yao Liu or Lianxin Liu.

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Liu, Y., Sun, L., Guo, H. et al. Targeting SLP2-mediated lipid metabolism reprograming restricts proliferation and metastasis of hepatocellular carcinoma and promotes sensitivity to Lenvatinib. Oncogene 42, 374–388 (2023). https://doi.org/10.1038/s41388-022-02551-z

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