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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.

Data availability

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

References

  1. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Son J, Lyssiotis CA, Ying HQ, Wang XX, Hua SJ, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;499:101–5.

    Article  Google Scholar 

  3. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW, et al. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA. 2012;109:8983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jin H, Wang S, Zaal EA, Wang C, Wu H, Bosma A, et al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. Elife. 2020;9:e56749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cormerais Y, Massard PA, Vucetic M, Giuliano S, Tambutte E, Durivault J, et al. The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5). J Biol Chem. 2018;293:2877–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sun HW, Yu XJ, Wu WC, Chen J, Shi M, Zheng LM, et al. GLUT1 and ASCT2 as predictors for prognosis of hepatocellular carcinoma. PLoS ONE. 2016;11:e0168907.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest. 2013;123:3678–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Willems L, Jacque N, Jacquel A, Neveux N, Maciel TT, Lambert M, et al. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood. 2013;122:3521–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, et al. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene. 2016;35:3201–8.

    Article  PubMed  Google Scholar 

  11. Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med. 2018;24:194–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Colas C, Grewer C, Otte NJ, Gameiro A, Albers T, Singh K, et al. Ligand discovery for the alanine-serine-cysteine transporter (ASCT2, SLC1A5) from homology modeling and virtual screening. PLoS Comput Biol. 2015;11:e1004477.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schifferli KP, Monks NR, Tammali R, Borrok MJ, Flynn MG, Hurt EM, et al. MEDI7247: a first in class antibody drug conjugate targeting ASCT2 in a range of solid tumors. Cancer Res. 2018;78:LB-298.

    Article  Google Scholar 

  14. Broer A, Fairweather S, Broer S. Disruption of amino acid homeostasis by novel ASCT2 inhibitors involves multiple targets. Front Pharm. 2018;9:785.

    Article  Google Scholar 

  15. Pore N, Schifferli KP, Monks NR, Tammali R, Borrok M, Hurt E, et al. Discovery and development of MEDI7247, a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological cancers. Blood. 2018;132:4071.

    Article  Google Scholar 

  16. Reynolds MR, Lane AN, Robertson B, Kemp S, Liu Y, Hill BG, et al. Control of glutamine metabolism by the tumor suppressor Rb. Oncogene. 2014;33:556–66.

    Article  CAS  PubMed  Google Scholar 

  17. Jeon YJ, Khelifa S, Ratnikov B, Scott DA, Feng Y, Parisi F, et al. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell. 2015;27:354–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee DE, Yoo JE, Kim J, Kim S, Kim S, Lee H, et al. NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter. Cell Death Dis. 2020;11:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Console LSM, Tarmakova Z, Coe IR, Indiveri C. N-linked glycosylation of human SLC1A5 (ASCT2) transporter is critical for trafficking to membrane. Biochim Biophys Acta. 2015;1853:1636–45.

    Article  CAS  PubMed  Google Scholar 

  20. Cooper-Knock J, Robins H, Niedermoser I, Wyles M, Heath PR, Higginbottom A, et al. Targeted genetic screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype. Front Mol Neurosci. 2017;10:370.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tamada H, Sakashita E, Shimazaki K, Ueno E, Hamamoto T, Kagawa Y, et al. cDNA cloning and characterization of Drb1, a new member of RRM-type neural RNA-binding protein. Biochem Biophys Res Commun. 2002;297:96–104.

  22. Choi SH, Flamand MN, Liu B, Zhu H, Hu M, Wang M, et al. RBM45 is an m(6)A-binding protein that affects neuronal differentiation and the splicing of a subset of mRNAs. Cell Rep. 2022;40:111293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mashiko T, Sakashita E, Kasashima K, Tominaga K, Kuroiwa K, Nozaki Y, et al. Developmentally regulated RNA-binding protein 1 (Drb1)/RNA-binding motif protein 45 (RBM45), a nuclear-cytoplasmic trafficking protein, forms TAR DNA-binding protein 43 (TDP-43)-mediated cytoplasmic aggregates. J Biol Chem. 2016;291:14996–5007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen X, Yang Z, Wang W, Qian K, Liu M, Wang J, et al. Structural basis for RNA recognition by the N-terminal tandem RRM domains of human RBM45. Nucleic Acids Res. 2021;49:2946–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gong J, Huang M, Wang F, Ma X, Liu H, Tu Y, et al. RBM45 competes with HDAC1 for binding to FUS in response to DNA damage. Nucleic Acids Res. 2017;45:12862–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bakkar N, Kousari A, Kovalik T, Li Y, Bowser R. RBM45 modulates the antioxidant response in amyotrophic lateral sclerosis through interactions with KEAP1. Mol Cell Biol. 2015;35:2385–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. del Rio-Moreno M, Alors-Perez E, Gonzalez-Rubio S, Ferrin G, Reyes O, Rodriguez-Peralvarez M, et al. Dysregulation of the splicing machinery is associated to the development of nonalcoholic fatty liver disease. J Clin Endocr Metab. 2019;104:3389–402.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ma RH, Zhang WG, Tang K, Zhang HF, Zhang Y, Li DP, et al. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. Nat Commun. 2013;4:2508.

    Article  PubMed  Google Scholar 

  29. Liu Q, Li J, Zhang W, Xiao C, Zhang S, Nian C, et al. Glycogen accumulation and phase separation drives liver tumor initiation. Cell. 2021;184:5559–76.e19.

    Article  CAS  PubMed  Google Scholar 

  30. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009;136:521–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Saito Y, Li L, Coyaud E, Luna A, Sander C, Raught B, et al. LLGL2 rescues nutrient stress by promoting leucine uptake in ER(+) breast cancer. Nature. 2019;569:275–9.

    Article  CAS  PubMed  Google Scholar 

  32. Fuchs BC, Finger RE, Onan MC, Bode BP. ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells. Am J Physiol Cell Physiol. 2007;293:C55–63.

    Article  CAS  PubMed  Google Scholar 

  33. Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 2020;31:267–83.e12.

    Article  CAS  PubMed  Google Scholar 

  34. Martinez Molina D, Jafari R, Ignatushchenko M, Seki T, Larsson EA, Dan C, et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science. 2013;341:84–7.

    Article  PubMed  Google Scholar 

  35. Esslinger CS, Cybulski KA, Rhoderick JF. N-gamma-Aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site. Bioorg Med Chem. 2005;13:1111–8.

    Article  CAS  PubMed  Google Scholar 

  36. Oppedisano F, Catto M, Koutentis PA, Nicolotti O, Pochini L, Koyioni M, et al. Inactivation of the glutamine/amino acid transporter ASCT2 by 1,2,3-dithiazoles: proteoliposomes as a tool to gain insights in the molecular mechanism of action and of antitumor activity. Toxicol Appl Pharm. 2012;265:93–102.

    Article  CAS  Google Scholar 

  37. Hara Y, Minami Y, Yoshimoto S, Hayashi N, Yamasaki A, Ueda S, et al. Anti-tumor effects of an antagonistic mAb against the ASCT2 amino acid transporter on KRAS-mutated human colorectal cancer cells. Cancer Med. 2020;9:302–12.

    Article  CAS  PubMed  Google Scholar 

  38. Garibsingh RAA, Ndaru E, Garaeva AA, Shi YY, Zielewicz L, Zakrepine P, et al. Rational design of ASCT2 inhibitors using an integrated experimental-computational approach. Proc Natl Acad Sci USA. 2021;118:e2104093118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dong Y, Wang JL, Eisenberg G, Yu XZ, Schlessinger A, Grewer CT. Conserved allosteric binding pocket in SLC1 glutamate transporter EAAT1 and neutral amino acid transporter ASCT2. Biophys J. 2022;121:250a.

    Article  Google Scholar 

  40. Yu W, Huang JW, Dong QC, Li WT, Jiang L, Zhang Q, et al. Ag120-mediated inhibition of ASCT2-dependent glutamine transport has an anti-tumor effect on colorectal cancer cells. Front Pharm. 2022;13:871392.

    Article  CAS  Google Scholar 

  41. Xu D, Hemler ME. Metabolic activation-related CD147-CD98 complex. Mol Cell Proteom. 2005;4:1061–71.

    Article  CAS  Google Scholar 

  42. Tao XA, Lu Y, Qiu SB, Wang Y, Qin J, Fan Z. AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis. Cancer Lett. 2017;408:33–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang Z, Follett J, Kerr MC, Clairfeuille T, Chandra M, Collins BM, et al. Sorting nexin 27 (SNX27) regulates the trafficking and activity of the glutamine transporter ASCT2. J Biol Chem. 2018;293:6802–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhou Q, Lin W, Wang C, Sun F, Ju S, Chen Q, et al. Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3(SPOP) E3 ligase in cancer cells. Nat Commun. 2022;13:3034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Clairfeuille T, Mas C, Chan AS, Yang Z, Tello-Lafoz M, Chandra M, et al. A molecular code for endosomal recycling of phosphorylated cargos by the SNX27-retromer complex. Nat Struct Mol Biol. 2016;23:921–32.

    Article  CAS  PubMed  Google Scholar 

  46. Pan YL, Han MZ, Zhang XC, He Y, Yuan CY, Xiong YX, et al. Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of SLC1A5 and the mTORC1 signaling pathway. Cell Oncol. 2022;45:163–78.

    Article  CAS  Google Scholar 

  47. Avissar NE, Sax HC, Toia L. In human entrocytes, GLN transport and ASCT2 surface expression induced by short-term EGF are MAPK, PI3K, and Rho-dependent. Dig Dis Sci. 2008;53:2113–25.

    Article  CAS  PubMed  Google Scholar 

  48. Li Y, Collins M, Geiser R, Bakkar N, Riascos D, Bowser R. RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules. Sci Rep. 2015;5:14262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang MS, Chang JH, Lin WC, Cheng YH, Li FA, Suen CS, et al. SLC38A2 overexpression induces a cancer-like metabolic profile and cooperates with SLC1A5 in Pan-cancer prognosis. Chem Asian J 2020;15:3861–72.

    Article  CAS  PubMed  Google Scholar 

  50. Yen K, Travins J, Wang F, David MD, Artin E, Straley K, et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017;7:478–93.

    Article  CAS  PubMed  Google Scholar 

  51. Wu Y, Du H, Zhan M, Wang H, Chen P, Du D, et al. Sepiapterin reductase promotes hepatocellular carcinoma progression via FoxO3a/Bim signaling in a nonenzymatic manner. Cell Death Dis. 2020;11:248.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tward AD, Jones KD, Yant S, Cheung ST, Fan ST, Chen X, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci USA. 2007;104:14771–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen X, Calvisi DF. Hydrodynamic transfection for generation of novel mouse models for liver cancer research. Am J Pathol. 2014;184:912–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Du H, Chen Y, Hou X, Huang Y, Wei X, Yu X, et al. PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC. Cell Death Dis. 2017;8:e3143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wei X, Li S, He J, Du H, Liu Y, Yu W, et al. Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling. Cell Commun Signal. 2019;17:58.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Fu T, Zhang M, Zhou Z, Wu P, Peng C, Wang Y, et al. Structural and biochemical advances on the recruitment of the autophagy-initiating ULK and TBK1 complexes by autophagy receptor NDP52. Sci Adv. 2021;7:eabi6582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Li H, Sun L, Li H, Lv X, Semukunzi H, Li R, et al. DT-13 synergistically enhanced vinorelbine-mediated mitotic arrest through inhibition of FOXM1-BICD2 axis in non-small-cell lung cancer cells. Cell Death Dis. 2017;8:e2810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang Q, Bailey CG, Ng C, Tiffen J, Thoeng A, Minhas V, et al. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res. 2011;71:7525–36.

    Article  CAS  PubMed  Google Scholar 

  59. Wang Z, Zhang Z, Li Y, Sun L, Peng D, Du D, et al. Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China. Acta Pharm Sin B. 2021;11:1526–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hashimoto M, Girardi E, Eichner R, Superti-Furga G. Detection of chemical engagement of solute carrier proteins by a cellular thermal shift assay. ACS Chem Biol. 2018;13:1480–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tang Z, Xie H, Heier C, Huang J, Zheng Q, Eichmann TO, et al. Enhanced monoacylglycerol lipolysis by ABHD6 promotes NSCLC pathogenesis. EBioMedicine. 2020;53:102696.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Pang ZQ, Zhou GY, Ewald J, Chang L, Hacariz O, Basu N, et al. Using MetaboAnalyst 5.0 for LC-HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data. Nat Protoc. 2022;17:1735–61.

    Article  CAS  PubMed  Google Scholar 

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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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