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RNA binding motif protein 45-mediated phosphorylation enhances protein stability of ASCT2 to promote hepatocellular carcinoma progression

Oncogene volume 42, pages 3127–3141 (2023)Cite this article

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Abstract

Targeting metabolic remodeling represents a potentially promising strategy for hepatocellular carcinoma (HCC) therapy. In-depth understanding on the regulation of the glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2) contributes to the development of novel promising therapeutics. As a developmentally regulated RNA binding protein, RBM45 is capable to shuttle between nucleus and cytoplasm, and directly interacts with proteins. By bioinformatics analysis, we screened out that RBM45 was elevated in the HCC patient specimens and positively correlated with poor prognosis. RBM45 promoted cell proliferation, boosted xenograft tumorigenicity and accelerated HCC progression. Using untargeted metabolomics, it was found that RBM45 interfered with glutamine metabolism. Further results demonstrated that RBM45 positively associated with ASCT2 in human and mouse specimens. Moreover, RBM45 enhanced ASCT2 protein stability by counteracting autophagy-independent lysosomal degradation. Significantly, wild-type ASCT2, instead of phospho-defective mutants, rescued siRBM45-suppressed HCC cell proliferation. Using molecular docking approaches, we found AG-221, a mutant isocitrate dehydrogenase 2 (mIDH2) inhibitor for acute myeloid leukemia therapy, pharmacologically perturbed RBM45-ASCT2 interaction, decreased ASCT2 stability and suppressed HCC progression. These findings provide evidence that RBM45 plays a crucial role in HCC progression via interacting with and counteracting the degradation of ASCT2. Our findings suggest a novel alternative structural sites for the design of ASCT2 inhibitors and the agents interfering with RBM45-ASCT2 interaction may be a potential direction for HCC drug development.

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Fig. 1: RBM45 positively correlates with poor prognosis of HCC and its liver-specific overexpression promotes HCC progression.
Fig. 2: RBM45 regulates glutamine metabolism and positively correlates with ASCT2 protein in HCC.
Fig. 3: Knockdown of RBM45 inhibits the proliferation of HCC.
Fig. 4: RBM45 binds to ASCT2 and RBM45 knockdown accelerates the turnover of ASCT2 protein through autophagy-independent lysosomal degradation.
Fig. 5: RBM45 disruption-mediated dephosphorylation of ASCT2 on SER493 and SER539 decreases ASCT2 protein stability in HCC cells.
Fig. 6: Delayed tumor growth by inhibition of RBM45 is recovered by wtASCT2 overexpression, not ASCT2 S493A or S539A.
Fig. 7: AG-221 accelerates ASCT2 protein degradation and suppresses HCC progression by interfering with RBM45-ASCT2 axis.

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Source data and reagents are available from the corresponding author upon reasonable request.

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Acknowledgements

The study was supported by the National Natural Science Foundation of China (Nos. 82070883, 82273982, 81872892), the Natural Science Foundation of Jiangsu Province, China (BK20221525) and Scientific Research Foundation for high-level faculty, China Pharmaceutical University. We thank all the financial support for this project and Dr. Xin Chen (UCSF) for sharing the oncogene plasmids.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Danyu Du, Mengyao Qin, Li Shi, Chan Liu, Hui Fan & Jing Xiong

  2. Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, 210009, China

    Danyu Du, Mengyao Qin, Chan Liu, Zhengguang Liao, Hongxv Wang, Zhibo Zhang, Li Sun, Zhengrui Liu, Jun Peng, Shengtao Yuan & Mei Yang

  3. Shuangyun BioMed Sci & Tech Co., Ltd., Suzhou, 215000, China

    Jingwei Jiang

  4. Department of Pathology, Taizhou People’s Hospital Affiliated to Dalian Medical University, Taizhou, 225300, Jiangsu, China

    Hong Yu

  5. Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, 210042, China

    Hongyang Li

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Contributions

DYD, MY, MYQ, L Shi and CL performed the research; ZGL, HXW, ZBZ, ZRL, HYL and JP conducted some experiments; JWJ performed molecular docking and MD simulations; HY collected clinical specimens; HF drew the graphical abstract; JX and STY designed the research study; JX and STY contributed essential reagents or tools; DYD, JX, L Sun and MY analyzed the data; JX, DYD and STY wrote the paper.

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Correspondence to Shengtao Yuan, Mei Yang or Jing Xiong.

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Du, D., Qin, M., Shi, L. et al. RNA binding motif protein 45-mediated phosphorylation enhances protein stability of ASCT2 to promote hepatocellular carcinoma progression. Oncogene 42, 3127–3141 (2023). https://doi.org/10.1038/s41388-023-02795-3

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