Molecular Mechanism of LSD1 Inhibition-mediated Selective Chromatin Opening: Specific Regulation of Tumor Differentiation-related Loci and Clinical Implications

Main Article Content

Zhihan Yang
Northeastern Agriculture University, Harbin, China

DOI: https://doi.org/10.70267/shbe.20260108

Keywords

LSD1, acute myeloid leukemia (AML), chromatin remodeling, differentiation therapy, epigenetic regulation

Abstract

Acute Myeloid Leukemia (AML) is characterized by a differentiation block of hematopoietic cells, with Lysine-Specific Demethylase 1 (LSD1) emerging as a key epigenetic regulator that silences myeloid differentiation genes to maintain leukemic stem cell stemness. This review elucidates the molecular mechanisms of LSD1 inhibition-mediated selective chromatin opening in AML therapy, including LSD1’s structural basis and its assembly in CoREST and NuRD repressive complexes. LSD1 inhibitors act by disrupting the LSD1-GFI1 interaction via steric hindrance, triggering NuRD-to-SWI/SNF chromatin remodeling switch, and reactivating PU.1/C/EBPα-dependent myeloid enhancers. Beyond histone demethylation, LSD1 modulates non-histone substrates (p53, DNMT1, E2F1, STAT3) to regulate cell apoptosis, DNA methylation, and the cell cycle. We further discuss translational advances, such as PROTAC degraders and combination regimens, as well as clinical challenges, including hematologic toxicities and drug resistance. This review highlights LSD1 as a promising epigenetic target and mechanistically informed combination therapies as the future direction for unlocking the AML differentiation block and improving clinical outcomes.

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References

  • [1] Testa, U., Castelli, G., & Pelosi, E. (2025). Recent Developments in Differentiation Therapy of Acute Myeloid Leukemia. Cancers, 17(7), 1141. https://doi.org/10.3390/cancers17071141
  • [2] Nong, T., Mehra, S., & Taylor, J. (2024). Common Driver Mutations in AML: Biological Impact, Clinical Considerations, and Treatment Strategies. Cells, 13(16), 1392. https://doi.org/10.3390/cells13161392
  • [3] Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J. R., Cole, P. A., Casero, R. A., & Shi, Y. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 119(7), 941–953. https://doi.org/10.1016/j.cell.2004.12.012
  • [4] Hosseini, A., Dhall, A., Ikonen, N., Sikora, N., Nguyen, S., Shen, Y., Amaral, M. L. J., Jiao, A., Wallner, F., Sergeev, P., Lim, Y., Yang, Y., Vick, B., Kawabata, K. C., Melnick, A., Vyas, P., Ren, B., Jeremias, I., Psaila, B., Heckman, C. A., … Shi, Y. (2025). Perturbing LSD1 and WNT rewires transcription to induce AML differentiation synergistically. Nature, 642(8067), 508–518. https://doi.org/10.1038/s41586-025-08915-1
  • [5] De Thé H. (2018). Differentiation therapy revisited. Nature Reviews. Cancer, 18(2), 117–127. https://doi.org/10.1038/nrc.2017.103
  • [6] Maiques-Diaz, A., & Somervaille, T. C. (2016). LSD1: Biologic Roles and Therapeutic Targeting. Epigenomics, 8(8), 1103–1116. https://doi.org/10.2217/epi-2016-0009
  • [7] Chen, Y., Yang, F., Wang, K., Wan, K., Yamane, Y., Zhang, Y., & Lei, M., Crystal structure of human histone lysine-specific demethylase 1 (LSD1), Proc. Natl. Acad. Sci. U.S.A. 103 (38) 13956-13961, https://doi.org/10.1073/pnas.0606381103 (2006).
  • [8] Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J. R., Cole, P. A., Casero, R. A., & Shi, Y. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 119(7), 941–953. https://doi.org/10.1016/j.cell.2004.12.012
  • [9] Noce, B., Di Bello, E., Fioravanti, R., & Mai, A. (2023). LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. Frontiers in pharmacology, 14, 1120911. https://doi.org/10.3389/fphar.2023.1120911
  • [10] Yang, M., Gocke, C. B., Luo, X., Borek, D., Tomchick, D. R., Machius, M., Otwinowski, Z., & Yu, H. (2006). Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Molecular Cell, 23(3), 377–387. https://doi.org/10.1016/j.molcel.2006.07.012
  • [11] Song, Y., Dagil, L., Fairall, L., Robertson, N., Wu, M., Ragan, T. J., Savva, C. G., Saleh, A., Morone, N., Kunze, M. B. A., Jamieson, A. G., Cole, P. A., Hansen, D. F., & Schwabe, J. W. R. (2020). Mechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex. Cell reports, 30(8), 2699–2711.e8. https://doi.org/10.1016/j.celrep.2020.01.091
  • [12] Marques, J. G., Gryder, B. E., Pavlovic, B., Chung, Y., Ngo, Q. A., Frommelt, F., Gstaiger, M., Song, Y., Benischke, K., Laubscher, D., Wachtel, M., Khan, J., & Schäfer, B. W. (2020). NuRD subunit CHD4 regulates super-enhancer accessibility in rhabdomyosarcoma and represents a general tumor dependency. eLife, 9, e54993. https://doi.org/10.7554/eLife.54993
  • [13] Cusan, M., Cai, S. F., Mohammad, H. P., Krivtsov, A., Chramiec, A., Loizou, E., Witkin, M. D., Smitheman, K. N., Tenen, D. G., Ye, M., Will, B., Steidl, U., Kruger, R. G., Levine, R. L., Rienhoff, H. Y., Jr, Koche, R. P., & Armstrong, S. A. (2018). LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML. Blood, 131(15), 1730–1742. https://doi.org/10.1182/blood-2017-09-807024
  • [14] Hartung, E. E., Singh, K., & Berg, T. (2023). LSD1 inhibition modulates transcription factor networks in myeloid malignancies. Frontiers in oncology, 13, 1149754. https://doi.org/10.3389/fonc.2023.1149754
  • [15] Beauchemin, H., & Möröy, T. (2020). Multifaceted Actions of GFI1 and GFI1B in Hematopoietic Stem Cell Self-Renewal and Lineage Commitment. Frontiers in genetics, 11, 591099. https://doi.org/10.3389/fgene.2020.591099
  • [16] Maiques-Diaz, A., Spencer, G. J., Lynch, J. T., Ciceri, F., Williams, E. L., Amaral, F. M. R., Wiseman, D. H., Harris, W. J., Li, Y., Sahoo, S., Hitchin, J. R., Mould, D. P., Fairweather, E. E., Waszkowycz, B., Jordan, A. M., Smith, D. L., & Somervaille, T. C. P. (2018). Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia. Cell reports, 22(13), 3641–3659. https://doi.org/10.1016/j.celrep.2018.03.012
  • [17] Nicosia, L., Boffo, F. L., Ceccacci, E., Conforti, F., Pallavicini, I., Bedin, F., Ravasio, R., Massignani, E., Somervaille, T. C. P., Minucci, S., & Bonaldi, T. (2022). Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML. Oncogene, 41(6), 878–894. https://doi.org/10.1038/s41388-021-02123-7
  • [18] Zhang, Y., Guo, N., Zhu, H., Liu, M., Hao, J., Wang, S., Guo, T., Mamun, M., Pang, J., Liu, Q., Zheng, Y., Liu, H., Si, P., & Zhao, L. (2024). Unlocking the dual role of LSD1 in tumor immunity: innate and adaptive pathways. Theranostics, 14(18), 7054–7071. https://doi.org/10.7150/thno.102037

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Published
May 20, 2026
Conference Proceedings Volume
Vol. 18 (2026): Proceedings of 2026 International Conference on Smart Healthcare and Biomedical Engineering (ICSHBE 2026)
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Articles
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How to Cite

Yang, Zhihan. “Molecular Mechanism of LSD1 Inhibition-Mediated Selective Chromatin Opening: Specific Regulation of Tumor Differentiation-Related Loci and Clinical Implications”. Exploring Science Academic Conference Series, vol. 18, May 2026, pp. 1-8, https://doi.org/10.70267/shbe.20260108.