LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2019 Nov 24

PMID 31756917

Citations 48

Authors

Panagiotis Karakaidos

John Verigos

Angeliki Magklara

Affiliations

Soon will be listed here.

Abstract

A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1's role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives.

Citing Articles

Cancer stem cells and niches: challenges in immunotherapy resistance.

Pan Y, Yuan C, Zeng C, Sun C, Xia L, Wang G Mol Cancer. 2025; 24(1):52.

PMID: 39994696 PMC: 11852583. DOI: 10.1186/s12943-025-02265-2.

Centromere inactivation during aging can be rescued in human cells.

Sikder S, Baek S, McNeil T, Dalal Y Mol Cell. 2025; 85(4):692-707.e7.

PMID: 39809271 PMC: 11852275. DOI: 10.1016/j.molcel.2024.12.018.

Inhibition of lysine-specific histone demethylase 1A suppresses adenomyosis through reduction in ectopic endometrial stromal cell proliferation, migration, and invasion.

Cui L, Sang C, Li R, Zhao S Cytojournal. 2024; 21:50.

PMID: 39737119 PMC: 11683409. DOI: 10.25259/Cytojournal_48_2024.

[ORY-1001 inhibits glioblastoma cell growth by downregulating the Notch/HES1 pathway suppressing lysine-specific demethylase 1 expression].

Yang H, Xiang Y, Tan T, Lei Y Nan Fang Yi Ke Da Xue Xue Bao. 2024; 44(8):1620-1630.

PMID: 39276059 PMC: 11378054. DOI: 10.12122/j.issn.1673-4254.2024.08.22.

Promising therapy for neuroendocrine prostate cancer: current status and future directions.

Fei X, Xue J, Wu J, Yang C, Wang K, Ma Q Ther Adv Med Oncol. 2024; 16:17588359241269676.

PMID: 39131727 PMC: 11311189. DOI: 10.1177/17588359241269676.

References

Myrick D, Christopher M, Scott A, Simon A, Donlin-Asp P, Kelly W . KDM1A/LSD1 regulates the differentiation and maintenance of spermatogonia in mice. PLoS One. 2017; 12(5):e0177473. PMC: 5428937. DOI: 10.1371/journal.pone.0177473. View

Rose A, Bradley A, Valasatava Y, Duarte J, Prlic A, Rose P . NGL viewer: web-based molecular graphics for large complexes. Bioinformatics. 2018; 34(21):3755-3758. PMC: 6198858. DOI: 10.1093/bioinformatics/bty419. View

Thambyrajah R, Mazan M, Patel R, Moignard V, Stefanska M, Marinopoulou E . GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1. Nat Cell Biol. 2015; 18(1):21-32. DOI: 10.1038/ncb3276. View

Lin Y, Wu Y, Li J, Dong C, Ye X, Chi Y . The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J. 2010; 29(11):1803-16. PMC: 2885925. DOI: 10.1038/emboj.2010.63. View

Hsu H, Liu Y, Tseng K, Yang T, Yeh C, You J . CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression. J Cancer Res Clin Oncol. 2014; 141(1):11-21. DOI: 10.1007/s00432-014-1782-4. View

Kalin J, Wu M, Gomez A, Song Y, Das J, Hayward D . Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nat Commun. 2018; 9(1):53. PMC: 5754352. DOI: 10.1038/s41467-017-02242-4. View

Mahmoudi E, Cairns M . MiR-137: an important player in neural development and neoplastic transformation. Mol Psychiatry. 2016; 22(1):44-55. PMC: 5414082. DOI: 10.1038/mp.2016.150. View

Musri M, Carmona M, Hanzu F, Kaliman P, Gomis R, Parrizas M . Histone demethylase LSD1 regulates adipogenesis. J Biol Chem. 2010; 285(39):30034-41. PMC: 2943311. DOI: 10.1074/jbc.M110.151209. View

Martello G, Smith A . The nature of embryonic stem cells. Annu Rev Cell Dev Biol. 2014; 30:647-75. DOI: 10.1146/annurev-cellbio-100913-013116. View

10.

Liu C, Liu L, Chen X, Cheng J, Zhang H, Zhang C . LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem-like Cells. Cancer Res. 2017; 78(4):938-949. DOI: 10.1158/0008-5472.CAN-17-1236. View

11.

Shi Y, Lie D, Taupin P, Nakashima K, Ray J, Yu R . Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature. 2004; 427(6969):78-83. DOI: 10.1038/nature02211. View

12.

Wada T, Koyama D, Kikuchi J, Honda H, Furukawa Y . Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation. Blood. 2015; 125(24):3731-46. DOI: 10.1182/blood-2014-11-610907. View

13.

Huang M, Chen C, Geng J, Han D, Wang T, Xie T . Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma. Cancer Lett. 2017; 398:12-21. DOI: 10.1016/j.canlet.2017.03.038. View

14.

Hoang N, Zhang X, Zhang C, Vo V, Leng F, Saxena L . New histone demethylase LSD1 inhibitor selectively targets teratocarcinoma and embryonic carcinoma cells. Bioorg Med Chem. 2018; 26(8):1523-1537. PMC: 6071666. DOI: 10.1016/j.bmc.2018.01.031. View

15.

Greer E, Shi Y . Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012; 13(5):343-57. PMC: 4073795. DOI: 10.1038/nrg3173. View

16.

Tosic M, Allen A, Willmann D, Lepper C, Kim J, Duteil D . Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells. Nat Commun. 2018; 9(1):366. PMC: 5785540. DOI: 10.1038/s41467-017-02740-5. View

17.

Verigos J, Karakaidos P, Kordias D, Papoudou-Bai A, Evangelou Z, Harissis H . The Histone Demethylase LSD1/ΚDM1A Mediates Chemoresistance in Breast Cancer via Regulation of a Stem Cell Program. Cancers (Basel). 2019; 11(10). PMC: 6827056. DOI: 10.3390/cancers11101585. View

18.

Maiques-Diaz A, Spencer G, Lynch J, Ciceri F, Williams E, Amaral F . Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia. Cell Rep. 2018; 22(13):3641-3659. PMC: 5896174. DOI: 10.1016/j.celrep.2018.03.012. View

19.

Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine G . Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature. 2007; 446(7138):882-7. DOI: 10.1038/nature05671. View

20.

Rice K, Hormaeche I, Licht J . Epigenetic regulation of normal and malignant hematopoiesis. Oncogene. 2007; 26(47):6697-714. DOI: 10.1038/sj.onc.1210755. View