Open Access Review

Overcoming MTDH and MTDH-SND1 complex: driver and potential therapeutic target of cancer

by Hao Shen a,b,c Jiayu Ding a,b,c Jiaying Ji a,b Binjian Jiang a,b Xiao Wang a,b,c,*  and  Peng Yang a,b,c,* orcid
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China
Author to whom correspondence should be addressed.
CI  2023, 29; 3(1), 29;
Received: 26 September 2023 / Accepted: 5 December 2023 / Published Online: 11 December 2023


Metadherin (MTDH), also known as LYRIC or AEG-1, is an oncogene that enhances tumor progression, metastasis, drug resistance, and immune escape in various cancers by modulating multiple oncogenic pathways, including NF-κB, PI3K/AKT, Wnt/β-catenin, MAPK, and AMPK. Due to the unknown of the complete structure of MTDH, the deep mechanisms of MTDH and selective inhibitors targeting MTDH remain to be explored. The Protein-Protein interaction (PPI) with the Staphylococcal nuclease domain containing 1 (SND1) is a crucial mechanism underlying the function of MTDH. Current studies have demonstrated that inhibitors, including antisense oligonucleotides, peptides, and small molecules targeting MTDH or MTDH-SND1 interactions, provide novel strategies to inhibit the oncogenetic effects of MTDH. This review summarizes and discusses the structure, function, and regulation of MTDH in cancers, providing the potential therapeutic perspectives of MTDH or MTDH-SND1 PPI for drug discovery.

Copyright: © 2023 by Shen, Ding, Ji, Jiang, Wang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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National Key R&D Program of China (2022YFA1303803) , National Natural Science Foundation of China (82073701) , Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZ202209)

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ACS Style
Shen, H.; Ding, J.; Ji, J.; Jiang, B.; Wang, X.; Yang, P. Overcoming MTDH and MTDH-SND1 complex: driver and potential therapeutic target of cancer. Cancer Insight, 2024, 3, 29.
AMA Style
Shen H, Ding J, Ji J, Jiang B, Wang X, Yang P. Overcoming MTDH and MTDH-SND1 complex: driver and potential therapeutic target of cancer. Cancer Insight; 2024, 3(1):29.
Chicago/Turabian Style
Shen, Hao; Ding, Jiayu; Ji, Jiaying; Jiang, Binjian; Wang, Xiao; Yang, Peng 2024. "Overcoming MTDH and MTDH-SND1 complex: driver and potential therapeutic target of cancer" Cancer Insight 3, no.1:29.
APA style
Shen, H., Ding, J., Ji, J., Jiang, B., Wang, X., & Yang, P. (2024). Overcoming MTDH and MTDH-SND1 complex: driver and potential therapeutic target of cancer. Cancer Insight, 3(1), 29.

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  1. Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J Clin 73, 17–48 (2023).
  2. Cortés-Ciriano, I., Gulhan, D. C., Lee, J. J.-K., Melloni, G. E. M. & Park, P. J. Computational analysis of cancer genome sequencing data. Nat Rev Genet 23, 298–314 (2022).
  3. Sriramulu, S. et al. Emerging Role and Clinicopathological Significance of AEG-1 in Different Cancer Types: A Concise Review. Cells 10, 1497 (2021).
  4. Li, M., Dai, Y., Wang, L. & Li, L. Astrocyte elevated gene-1 promotes the proliferation and invasion of breast cancer cells by activating the Wnt/β-catenin signaling pathway. Oncol Lett 13, 2385–2390 (2017).
  5. Lee, H.-J. et al. Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells. Evid Based Complement Alternat Med 2012, 390957 (2012).
  6. Yoo, B. K. et al. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest 119, 465–477 (2009).
  7. Ma, Z. et al. AEG-1 mRNA expression in non-small cell lung cancer is associated with increased tumor angiogenesis. Pathol Res Pract 213, 1257–1263 (2017).
  8. Du, Y. et al. Metadherin regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition. Int J Oncol 51, 63–74 (2017).
  9. Long, M. et al. Overexpression of astrocyte-elevated gene-1 is associated with cervical carcinoma progression and angiogenesis. Oncol Rep 30, 1414–1422 (2013).
  10. Wang, S.-S. et al. Metadherin Promotes the Development of Bladder Cancer by Enhancing Cell Division. Cancer Biother Radiopharm (2022).
  11. He, A. et al. MTDH promotes metastasis of clear cell renal cell carcinoma by activating SND1-mediated ERK signaling and epithelial-mesenchymal transition. Aging (Albany NY) 12, 1465–1487 (2020).
  12. Jian-bo, X. et al. Astrocyte-elevated gene-1 overexpression is associated with poor prognosis in gastric cancer. Med Oncol 28, 455–462 (2011).
  13. Gnosa, S. et al. AEG-1 expression is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy: a study in a Swedish clinical trial. Br J Cancer 111, 166–173 (2014).
  14. Liu, X. et al. MTDH in macrophages promotes the vasculogenic mimicry via VEGFA-165/Flt-1 signaling pathway in head and neck squamous cell carcinoma. Int Immunopharmacol 96, 107776 (2021).
  15. Li, J. et al. AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide. Sci Rep 11, 17348 (2021).
  16. Dhiman, G. et al. Metadherin: A Therapeutic Target in Multiple Cancers. Front Oncol 9, 349 (2019).
  17. Su, Z.-Z. et al. Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene 21, 3592–3602 (2002).
  18. Kang, D.-C. et al. Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene 353, 8–15 (2005).
  19. Hsu, J. C.-C., Reid, D. W., Hoffman, A. M., Sarkar, D. & Nicchitta, C. V. Oncoprotein AEG-1 is an endoplasmic reticulum RNA-binding protein whose interactome is enriched in organelle resident protein-encoding mRNAs. RNA 24, 688–703 (2018).
  20. Alexia, C. et al. The endoplasmic reticulum acts as a platform for ubiquitylated components of nuclear factor κB signaling. Sci Signal 6, ra79 (2013).
  21. Sarkar, D. et al. Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res 68, 1478–1484 (2008).
  22. Emdad, L. et al. Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. Pharmacol Ther 114, 155–170 (2007).
  23. Sutherland, H. G. E., Lam, Y. W., Briers, S., Lamond, A. I. & Bickmore, W. A. 3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus. Exp Cell Res 294, 94–105 (2004).
  24. Thirkettle, H. J. et al. LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals. Clin Cancer Res 15, 3003–3013 (2009).
  25. Luxton, H. J. et al. Regulation of the localisation and function of the oncogene LYRIC/AEG-1 by ubiquitination at K486 and K491. Mol Oncol 8, 633–641 (2014).
  26. Guo, F. et al. Structural insights into the tumor-promoting function of the MTDH-SND1 complex. Cell Rep 8, 1704–1713 (2014).
  27. Srivastava, J. et al. AEG-1 regulates retinoid X receptor and inhibits retinoid signaling. Cancer Res 74, 4364–4377 (2014).
  28. Zhu, K. et al. Metadherin-PRMT5 complex enhances the metastasis of hepatocellular carcinoma through the WNT-β-catenin signaling pathway. Carcinogenesis 41, 130–138 (2020).
  29. Brown, D. M. & Ruoslahti, E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5, 365–374 (2004).
  30. Thirkettle, H. J., Mills, I. G., Whitaker, H. C. & Neal, D. E. Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression. Oncogene 28, 3663–3670 (2009).
  31. Emdad, L. et al. Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 66, 1509–1516 (2006).
  32. Lee, S.-G., Su, Z.-Z., Emdad, L., Sarkar, D. & Fisher, P. B. Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci U S A 103, 17390–17395 (2006).
  33. Ash, S. C., Yang, D. Q. & Britt, D. E. LYRIC/AEG-1 overexpression modulates BCCIPalpha protein levels in prostate tumor cells. Biochem Biophys Res Commun 371, 333–338 (2008).
  34. Yang, L. et al. Metadherin/Astrocyte elevated gene-1 positively regulates the stability and function of forkhead box M1 during tumorigenesis. Neuro Oncol 19, 352–363 (2017).
  35. Li, K. et al. Proteomes from AMPK-inhibited peripheral blood mononuclear cells suppress the progression of breast cancer and bone metastasis. Theranostics 13, 1247–1263 (2023).
  36. Jia, Y. et al. Long non-coding RNA NORAD/miR-224-3p/MTDH axis contributes to CDDP resistance of esophageal squamous cell carcinoma by promoting nuclear accumulation of β-catenin. Mol Cancer 20, 162 (2021).
  37. Han, L. et al. Overcoming cisplatin resistance by targeting the MTDH-PTEN interaction in ovarian cancer with sera derived from rats exposed to Guizhi Fuling wan extract. BMC Complement Med Ther 20, 57 (2020).
  38. Jin, C. et al. MTDH-stabilized DDX17 promotes tumor initiation and progression through interacting with YB1 to induce EGFR transcription in Hepatocellular Carcinoma. Oncogene 42, 169–183 (2023).
  39. Kang, D., Lee, Y. & Lee, J.-S. RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives. Cancers (Basel) 12, 2699 (2020).
  40. Mohibi, S., Chen, X. & Zhang, J. Cancer the’RBP’eutics-RNA-binding proteins as therapeutic targets for cancer. Pharmacol Ther 203, 107390 (2019).
  41. Qin, H. et al. RNA-binding proteins in tumor progression. Journal of Hematology & Oncology 13, 90 (2020).
  42. Meng, X. et al. Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein. J Biol Chem 287, 4485–4491 (2012).
  43. Zhao, T. et al. HIF-1α binding to AEG-1 promoter induced upregulated AEG-1 expression associated with metastasis in ovarian cancer. Cancer Med 6, 1072–1081 (2017).
  44. Zhang, L. et al. Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling. Transl Oncol 12, 859–870 (2019).
  45. Mangan, S. & Alon, U. Structure and function of the feed-forward loop network motif. Proc Natl Acad Sci U S A 100, 11980–11985 (2003).
  46. Shi, X. et al. Increased HSF1 Promotes Infiltration and Metastasis in Cervical Cancer via Enhancing MTDH-VEGF-C Expression. Onco Targets Ther 14, 1305–1315 (2021).
  47. Komaniecki, G. et al. Astrocyte Elevated Gene-1 Cys75 S-Palmitoylation by ZDHHC6 Regulates Its Biological Activity. Biochemistry 62, 543–553 (2023).
  48. Zhou, B. et al. The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma. Theranostics 12, 6898–6914 (2022).
  49. Robertson, C. L. et al. Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis. Cancer Res 78, 6436–6446 (2018).
  50. Chen, X. et al. The FBXW7 tumor suppressor inhibits breast cancer proliferation and promotes apoptosis by targeting MTDH for degradation. Neoplasma 65, 201–209 (2018).
  51. Denuc, A. & Marfany, G. SUMO and ubiquitin paths converge. Biochem Soc Trans 38, 34–39 (2010).
  52. Zhang, H. et al. CPEB3-mediated MTDH mRNA translational suppression restrains hepatocellular carcinoma progression. Cell Death Dis 11, 792 (2020).
  53. He, B. et al. miRNA-based biomarkers, therapies, and resistance in Cancer. Int J Biol Sci 16, 2628–2647 (2020).
  54. Inoue, J. & Inazawa, J. Cancer-associated miRNAs and their therapeutic potential. J Hum Genet 66, 937–945 (2021).
  55. Lin, S. & Gregory, R. I. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15, 321–333 (2015).
  56. Ganesan, H. et al. RNA-Interference-Mediated miR-122-Based Gene Regulation in Colon Cancer, a Structural In Silico Analysis. Int J Mol Sci 23, 15257 (2022).
  57. Ahmed, E. A., Rajendran, P. & Scherthan, H. The microRNA-202 as a Diagnostic Biomarker and a Potential Tumor Suppressor. Int J Mol Sci 23, 5870 (2022).
  58. Wang, Y. et al. MiR-9-3p regulates the biological functions and drug resistance of gemcitabine-treated breast cancer cells and affects tumor growth through targeting MTDH. Cell Death Dis 12, 861 (2021).
  59. Banerjee, S., Kalyani Yabalooru, S. R. & Karunagaran, D. Identification of mRNA and non-coding RNA hubs using network analysis in organ tropism regulated triple negative breast cancer metastasis. Comput Biol Med 127, 104076 (2020).
  60. Saklani, N. et al. In silico analysis to identify novel ceRNA regulatory axes associated with gallbladder cancer. Front Genet 14, 1107614 (2023).
  61. Yang, L. et al. miR-217-5p suppresses epithelial-mesenchymal transition and the NF-κB signaling pathway in breast cancer via targeting of metadherin. Oncol Lett 23, 162 (2022).
  62. Jin, H., Wu, Z., Tan, B., Liu, Z. & Zhang, B. CircITGA7 Suppresses Gastric Cancer Progression Through miR-1471/MTDH Axis. Front Cell Dev Biol 9, 688970 (2021).
  63. Jiang, Z. et al. TNF-α-Induced miR-21-3p Promotes Intestinal Barrier Dysfunction by Inhibiting MTDH Expression. Front Pharmacol 12, 722283 (2021).
  64. Zhao, J., Zhou, K., Ma, L. & Zhang, H. MicroRNA-145 overexpression inhibits neuroblastoma tumorigenesis in vitro and in vivo. Bioengineered 11, 219–228 (2020).
  65. Chang, X.-S., Zhu, J., Yang, T. & Gao, Y. MiR-524 suppressed the progression of oral squamous cell carcinoma by suppressing Metadherin and NF-κB signaling pathway in OSCC cell lines. Arch Oral Biol 125, 105090 (2021).
  66. Zhang, S. et al. miR-30e-5p represses angiogenesis and metastasis by directly targeting AEG-1 in squamous cell carcinoma of the head and neck. Cancer Sci 111, 356–368 (2020).
  67. Sun, X., Zhai, H., Chen, X., Kong, R. & Zhang, X. MicroRNA-1271 suppresses the proliferation and invasion of colorectal cancer cells by regulating metadherin/Wnt signaling. J Biochem Mol Toxicol 32, (2018).
  68. Zhang, Z. et al. miR-30e-5p suppresses cell proliferation and migration in bladder cancer through regulating metadherin. J Cell Biochem 120, 15924–15932 (2019).
  69. Banerjee, I., Fisher, P. B. & Sarkar, D. Astrocyte elevated gene-1 (AEG-1): A key driver of hepatocellular carcinoma (HCC). Adv Cancer Res 152, 329–381 (2021).
  70. Chen, Y., Huang, S., Guo, R. & Chen, D. Metadherin-mediated mechanisms in human malignancies. Biomark Med 15, 1769–1783 (2021).
  71. Yu, C. et al. Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis 30, 894–901 (2009).
  72. Jung, H. I. et al. Astrocyte elevated gene-1 overexpression in hepatocellular carcinoma: an independent prognostic factor. Ann Surg Treat Res 88, 77–85 (2015).
  73. Yi, S., Zhang, C., Li, M. & Wang, J. Construction of a Novel Diagnostic Model Based on Ferroptosis-Related Genes for Hepatocellular Carcinoma Using Machine and Deep Learning Methods. J Oncol 2023, 1624580 (2023).
  74. Nasr, Z., Robert, F., Porco, J. A., Muller, W. J. & Pelletier, J. eIF4F suppression in breast cancer affects maintenance and progression. Oncogene 32, 861–871 (2013).
  75. Lai, E. C. H. & Lau, W. Y. Aggressive surgical resection for carcinoma of gallbladder. ANZ J Surg 75, 441–444 (2005).
  76. Wan, L. et al. MTDH-SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors. Cancer Cell 26, 92–105 (2014).
  77. Ortiz-Soto, G. et al. Metadherin Regulates Inflammatory Breast Cancer Invasion and Metastasis. Int J Mol Sci 24, 4694 (2023).
  78. Liu, H. et al. Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. J Exp Clin Cancer Res 28, 19 (2009).
  79. Wang, Q. et al. MicroRNA-98/PTEN/AKT pathway inhibits cell proliferation and malignant progression of hypopharyngeal carcinoma by MTDH. Oncol Rep. 41(2):863-874. (2018).
  80. Feng, D. et al. Metadherin Promotes Malignant Phenotypes And Induces Beta-Catenin Nuclear Translocation And Epithelial-Mesenchymal Transition In Gastric Cancer. Cancer Manag Res 11, 8911–8921 (2019).
  81. El-Ashmawy, N. E., El-Zamarany, E. A., Khedr, E. G. & Abo-Saif, M. A. Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway. Mol Cell Biochem 457, 83–91 (2019).
  82. Luo, L. et al. LINC01638 lncRNA activates MTDH-Twist1 signaling by preventing SPOP-mediated c-Myc degradation in triple-negative breast cancer. Oncogene 37, 6166–6179 (2018).
  83. Wei, J. et al. AEG-1 participates in TGF-beta1-induced EMT through p38 MAPK activation. Cell Biol Int 37, 1016–1021 (2013).
  84. Lai, T. H. et al. Transcriptional Repression of Raf Kinase Inhibitory Protein Gene by Metadherin during Cancer Progression. Int J Mol Sci 22, 3052 (2021).
  85. Lugano, R., Ramachandran, M. & Dimberg, A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77, 1745–1770 (2020).
  86. Khan, M. & Sarkar, D. The Scope of Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH) in Cancer Clinicopathology: A Review. Genes (Basel) 12, 308 (2021).
  87. Meng, X.-L. et al. The Proteome Landscape of Human Placentas for Monochorionic Twins with Selective Intrauterine Growth Restriction. Genomics Proteomics Bioinformatics S1672-0229(23)00071–2 (2023).
  88. Chen, S., Chen, L.-H., Niu, Y.-H., Geng, N.-B. & Feng, C.-J. AEG-1 promotes angiogenesis and may be a novel treatment target for tongue squamous cell carcinoma. Oral Dis 26, 876–884 (2020).
  89. Emdad, L. et al. Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis. Proc Natl Acad Sci U S A 106, 21300–21305 (2009).
  90. Neeli, P. K. et al. DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer: intermediacy of NF-κB-HIF1α axis. FEBS J 290, 502–520 (2023).
  91. Wang, X., Zhang, H. & Chen, X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist 2, 141–160 (2019).
  92. Holohan, C., Van Schaeybroeck, S., Longley, D. B. & Johnston, P. G. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13, 714–726 (2013).
  93. Vasan, N., Baselga, J. & Hyman, D. M. A view on drug resistance in cancer. Nature 575, 299–309 (2019).
  94. Eljack, S., David, S., Faggad, A., Chourpa, I. & Allard-Vannier, E. Nanoparticles design considerations to co-deliver nucleic acids and anti-cancer drugs for chemoresistance reversal. Int J Pharm X 4, 100126 (2022).
  95. Peng, K.-L. et al. Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance. Proc Natl Acad Sci U S A 119, e2203738119 (2022).
  96. Xia, H., Green, D. R. & Zou, W. Autophagy in tumour immunity and therapy. Nat Rev Cancer 21, 281–297 (2021).
  97. Mulcahy Levy, J. M. & Thorburn, A. Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ 27, 843–857 (2020).
  98. Bhutia, S. K. et al. Astrocyte elevated gene-1 induces protective autophagy. Proc Natl Acad Sci U S A 107, 22243–22248 (2010).
  99. Bhutia, S. K. et al. Astrocyte elevated gene-1 activates AMPK in response to cellular metabolic stress and promotes protective autophagy. Autophagy 7, 547–548 (2011).
  100. Manna, D. & Sarkar, D. Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance. Cancers (Basel) 13, 1792 (2021).
  101. Pei, G. et al. Autophagy Facilitates Metadherin-Induced Chemotherapy Resistance Through the AMPK/ATG5 Pathway in Gastric Cancer. Cell Physiol Biochem 46, 847–859 (2018).
  102. Zhang, J. et al. Metadherin confers chemoresistance of cervical cancer cells by inducing autophagy and activating ERK/NF-κB pathway. Tumour Biol 34, 2433–2440 (2013).
  103. Zhu, H.-D. et al. Astrocyte elevated gene 1 (AEG-1) promotes anoikis resistance and metastasis by inducing autophagy in hepatocellular carcinoma. J Cell Physiol 235, 5084–5095 (2020).
  104. Shen, M. et al. Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer. Nat Cancer 3, 60–74 (2022).
  105. Hu, B. et al. Astrocyte Elevated Gene-1 Regulates β-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal. Mol Cancer Res 15, 225–233 (2017).
  106. Zhang, F. et al. MTDH associates with m6A RNA methylation and predicts cancer response for immune checkpoint treatment. iScience 24, 103102 (2021).
  107. Ochoa, B., Chico, Y. & Martínez, M. J. Insights Into SND1 Oncogene Promoter Regulation. Front Oncol 8, 606 (2018).
  108. Wang, X. et al. Coactivator P100 protein enhances STAT6-dependent transcriptional activation but has no effect on STAT1-mediated gene transcription. Anat Rec (Hoboken) 293, 1010–1016 (2010).
  109. Su, C. et al. Tudor staphylococcal nuclease (Tudor-SN), a novel regulator facilitating G1/S phase transition, acting as a co-activator of E2F-1 in cell cycle regulation. J Biol Chem 290, 7208–7220 (2015).
  110. Callebaut, I. & Mornon, J. P. The human EBNA-2 coactivator p100: multidomain organization and relationship to the staphylococcal nuclease fold and to the tudor protein involved in Drosophila melanogaster development. Biochem J 321 ( Pt 1), 125–132 (1997).
  111. Bheda, A., Yue, W., Gullapalli, A., Shackelford, J. & Pagano, J. S. PU.1-dependent regulation of UCH L1 expression in B-lymphoma cells. Leuk Lymphoma 52, 1336–1347 (2011).
  112. Leverson, J. D. et al. Pim-1 kinase and p100 cooperate to enhance c-Myb activity. Mol Cell 2, 417–425 (1998).
  113. Gutierrez-Beltran, E., Denisenko, T. V., Zhivotovsky, B. & Bozhkov, P. V. Tudor staphylococcal nuclease: biochemistry and functions. Cell Death Differ 23, 1739–1748 (2016).
  114. Yang, J. et al. Transcriptional co-activator protein p100 interacts with snRNP proteins and facilitates the assembly of the spliceosome. Nucleic Acids Res 35, 4485–4494 (2007).
  115. Gao, X. et al. Tudor staphylococcal nuclease (Tudor-SN) participates in small ribonucleoprotein (snRNP) assembly via interacting with symmetrically dimethylated Sm proteins. J Biol Chem 287, 18130–18141 (2012).
  116. Jariwala, N. et al. Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma. Cancer Res 77, 3306–3316 (2017).
  117. Shao, J. et al. Aggregation of SND1 in Stress Granules is Associated with the Microtubule Cytoskeleton During Heat Shock Stimulus. Anat Rec (Hoboken) 300, 2192–2199 (2017).
  118. Gutierrez-Beltran, E., Moschou, P. N., Smertenko, A. P. & Bozhkov, P. V. Tudor staphylococcal nuclease links formation of stress granules and processing bodies with mRNA catabolism in Arabidopsis. Plant Cell 27, 926–943 (2015).
  119. Gao, X. et al. Tudor-SN interacts with and co-localizes with G3BP in stress granules under stress conditions. FEBS Lett 584, 3525–3532 (2010).
  120. Wei, Y. et al. Bidirectional Functional Effects of Staphylococcus on Carcinogenesis. Microorganisms 10, 2353 (2022).
  121. Tong, L. et al. Correlated overexpression of metadherin and SND1 in glioma cells. Biol Chem 397, 57–65 (2016).
  122. Wang, N. et al. Prognostic impact of Metadherin-SND1 interaction in colon cancer. Mol Biol Rep 39, 10497–10504 (2012).
  123. Yoo, B. K. et al. Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma. Hepatology 53, 1538–1548 (2011).
  124. Santhekadur, P. K. et al. Multifunction protein staphylococcal nuclease domain containing 1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves nuclear factor κB and miR-221. J Biol Chem 287, 13952–13958 (2012).Santhekadur, P. K. et al. 10.1074/jbc.M111.321646
  125. Crooke, S. T., Baker, B. F., Crooke, R. M. & Liang, X. Antisense technology: an overview and prospectus. Nat Rev Drug Discov 20, 427–453 (2021).
  126. Castanotto, D. & Stein, C. A. Antisense oligonucleotides in cancer. Curr Opin Oncol 26, 584–589 (2014).
  127. Shen, M. et al. Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis. Cancer Res 81, 1014–1025 (2021).
  128. Wan, J.-L. et al. MTDH antisense oligonucleotides reshape the immunosuppressive tumor microenvironment to sensitize Hepatocellular Carcinoma to immune checkpoint blockade therapy. Cancer Lett 541, 215750 (2022).
  129. Chen, H. et al. Structure-Based Design, Optimization, and Evaluation of Potent Stabilized Peptide Inhibitors Disrupting MTDH and SND1 Interaction. J Med Chem 65, 12188–12199 (2022). 10.1021/acs.jmedchem.2c00862
  130. Li, P. et al. Disruption of SND1-MTDH Interaction by a High Affinity Peptide Results in SND1 Degradation and Cytotoxicity to Breast Cancer Cells In Vitro and In Vivo. Mol Cancer Ther 20, 76–84 (2021).
  131. Shen, M. et al. Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis. Nat Cancer 3, 43–59 (2022).
  132. Xu, Y. et al. Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein-Protein Interaction. J Chem Inf Model 63, 3614–3627 (2023).
  133. Pang, P. et al. Exploring binding modes of the selected inhibitors to SND1 by all-atom molecular dynamics simulations. J Biomol Struct Dyn 1–15 (2023).
  134. Pavet, V., Portal, M. M., Moulin, J. C., Herbrecht, R. & Gronemeyer, H. Towards novel paradigms for cancer therapy. Oncogene 30, 1–20 (2011).
  135. Zhong, L. et al. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Sig Transduct Target Ther 6, 1–48 (2021).
  136. Yan, J.-W., Lin, J.-S. & He, X.-X. The emerging role of miR-375 in cancer. Int J Cancer 135, 1011–1018 (2014).
  137. Jayashree, S., Murugavel, P., Sowdhamini, R. & Srinivasan, N. Interface residues of transient protein-protein complexes have extensive intra-protein interactions apart from inter-protein interactions. Biology Direct 14, 1 (2019).
  138. Gurung, A. B., Ali, M. A., Lee, J., Farah, M. A. & Al-Anazi, K. M. An Updated Review of Computer-Aided Drug Design and Its Application to COVID-19. Biomed Res Int 2021, 8853056 (2021).
  139. Niu, Y. & Lin, P. Advances of computer-aided drug design (CADD) in the development of anti-Azheimer’s-disease drugs. Drug Discov Today 103665 (2023).
  140. Singer, M. & Anderson, A. C. Revolutionizing cancer immunology: the power of next-generation sequencing technologies. Cancer Immunol Res 7, 168–173 (2019).
  141. Hwang, B., Lee, J. H. & Bang, D. Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med 50, 1–14 (2018).