Reinhard Büttner / Margarete Odenthal - A 1

The multifaceted function of the lysine-specific histone demethylase 1 in lung cancer

Epigenetic abnormalities play a vital role in the progression of many cancer types including non-small cell lung cancer (NSCLC) which is a leading cause of cancer-related mortality. The lysine-specific demethylase 1 (LSD1/KDM1A) acts as an epigenetic regulator and is overexpressed in a wide variety of cancer types. In our studies, we address the mechanistic links of LSD1 function in NSCLC development using cancer-related cell systems and genetic mouse models. 


Deregulation of epigenetic mechanisms is a hallmark of cancer and contributes to cancer development and progression, where it can lead to altered gene function and malignant cell-transformation. Epigenetic mechanisms include changes in DNA methylation, alterations in pattern and function of non-coding RNAs as well as chromatin remodeling due to modification of histones. Histone methylation mediates transcriptional regulation by switching on or off gene expression. The lysine-specific demethylase 1 (LSD1) catalyzes the demethylation of the histone 3 (H3) subunits, namely H3K4 and H3K9, resulting in gene repression or activation, respectively. 

LSD1 is highly overexpressed in many cancer types including non-small cell lung cancer (NSCLC). NSCLC, representing 80% of all lung cancer types, is a leading cause of cancer related mortality. Importantly, our recent studies proved that LSD1 overexpression is associated with NSCLC malignancy (Lim et al. 2017). 

LSD1 inhibitors as novel therapeutic option

Since LSD1 acts as highly conserved flavin adenine dinucleotide (FAD)-dependent amine oxidase, demethylase activity can be blocked by monoamine oxidase (MAO) inhibitors and newly designed derivatives of them. Furthermore, other non-MAO LSD1 inhibitors are under development. Previously, we have used the y-pyrone Namoline to inhibit LSD1 function in prostate cancer cells (Willmann et al. 2012). The LSD1 inhibitor HCI-2509 is a novel and very potent non-MAO inhibitor, which reversibly binds to LSD1, but also disables LSD1 solubility, and blocks LSD1 interactions within the chromatin remodeling complex e.g. CoREST. 

Using various NSCLC-representing cell lines, the reversible LSD1 inhibitor HCI-2509 significantly reduced cell growth with an IC50 of 0.3 to 5 µM in vitro (Macheleidt et al. 2018). Most importantly, growth arrest as well as inhibition of the invasion capacities were independent of the underlying driver mutations such as activating KRAS or EGFR mutations (Figure 2). Expression profiling revealed that the cell cycle and replication machinery was prominently affected after LSD1 inhibition. Chromatin immunoprecipitation studies identified PLK1 as a direct target of LSD1 transcriptional regulation. 

These in vitro findings were confirmed by preclinical therapeutic approaches including two transgenic NSCLC mouse models driven by either an activating EGFR or a KRAS mutation. Importantly, LSD1 inhibition resulted in significantly lower tumor formation and a strong reduction in tumor progression which were independent of the underlying mutational background of the mouse models (Figure 2C-G) (Macheleidt et al. 2018). 

Hence, our findings provide substantial evidence that tumor growth of NSCLC can be markedly decreased by LSD1 inhibition, suggesting its therapeutical application in novel concerted drug approaches.


Interestingly, our data on non-small cell lung cancer (NSCLC) mouse models and cell culture systems supports recent reports that the histone-modifying machinery is not only crucial for transcriptional regulation, but also for mechanisms involved in DNA repair and in RNA processing. Most notably, the regulation of mRNA alternative splicing is closely linked to the histone-modified regulation of mRNA transcriptional elongation providing first evidence that histone modification also drives oncogenic signaling on the basis of alternative splicing and mRNA export processing. Comprehensive analysis of the histone methylation and the LSD1 binding signature, considering in particular the regions of exon junctions, will shed light on the mechanistic link of LSD1 to the splicing machinery. Hereby CRISPR-Cas modified LSD1 mutants will be used.

Selected publications (2017-2018)

1. Macheleidt I.F., Dalvi P.S., Lim S.Y., Meemboor S., Meder L., et al. Büttner R., and Odenthal M. (2018) Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations. Mol Oncol. 12(11):1965-1979.

2. Grasse S, Lienhard M, Frese S, Kerick M, Steinbach A, et al. Odenthal M, Büttner R, Lehrach H, Sültmann H, Herwig R, and Schweiger MR. (2018) Epigenomic pro-filing of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Med. J 10(1):55.

3. Lim S.Y., Macheleidt, I., Dalvi P., Schäfer S. et al. Tho-mas R.K., Schweiger M.R., Buettner R., and Odenthal M. (2017). LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells. Sci Rep. 7(1), 10292.

4. Meder L, König K, Dietlein F, Macheleidt I, Florin A, et al., Odenthal M, Klein F, Büttner R, Schulte JH, Heukamp LC, Ullrich RT. (2018) LIN28B enhanced tumorigenesis in an autochthonous KRASG12V-driven lung carcinoma mouse model. Oncogene 37:2746-2756.

5. Meder L, Büttner R, Odenthal M. Notch signaling triggers the tumor heterogeneity of small cell lung cancer. (2017) J Thorac Dis. 9(12):4884-4888. 

6. Amer W, Toth C, Vassella E, et al.  Buettner R, Scheel A, Schaefer SC, Odenthal M. (2017) Evolution analysis of heterogeneous non-small cell lung carcinoma by ultra-deep sequencing of the mitochondrial genome. Sci Rep. 11;7(1):11069.

7. Plenker D., Riedel M., Brägelmann J., et al. Buettner R., Shokat K.M., McDonald N.Q., Kast S.M., Gautschi O., Thomas R.K., Sos M.L. (2017) Drugging the catalyt-ically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med. 4 (9): 394-405.

8. Dalvi P.S., Macheleidt I.F., Lim SY., Meemboor S., et al., Buettner R., Klein, S. and Odenthal M. (2019) LSD1 inhibition attenuates tumor growth by disrupting PLK1 mitotic pathway. Mol Cancer Res. 2019 Feb 13. doi: 10.1158/1541-7786.MCR-18-0971.

Prof. Dr. Reinhard Büttner

Institute for Pathology

Prof. Dr. Reinhard Büttner

Principal Investigator A 1
Executive Board Member

Work +49 221 478 6320

Fax (Work) +49 221 478 6360

Institute for Pathology
Kerpener Str. 62
50937 Cologne

Publications - Reinhard Büttner

Link to PubMed

Prof. Dr. Margarete Odenthal

Institute for Pathology

Prof. Dr. Margarete Odenthal

Co-Principal Investigator A 1

Work +49 221 478 6351

Fax (Work) +49 221 478 6360

Institute for Pathology
Kerpener Str. 62
50937 Cologne

Publications - Margarete Odenthal

Link to PubMed

Group Members

Dr. Sonja Meemboor (Scientific Coordinator)
Dr. Priya Dalvi (Post-Doc)
Dr. Maria Anokhina (Post-Doc)
Marcel Schmiel (MD candidate)
Miriam Weiß (MD candidate)
Lingyu Wang (MD, PhD candidate)
Ulrike Koitzsch (BA, TA)
Hannah Eischeidt-Scholz (TA)

Figure 1

CMMC Research Odenthal
LSD1 overexpression in NSCLC is associated with NSCLC progression and malignancy

Figure 2

CMMC Research Odenthal
Tumor cell growth arrest upon LSD1 inhibition Cell growth was inhibited in different NSCLC cell lines by the LSD1 inhibitor HCI2509 (A) due to cell cycle arrest (B). Two transgenic mouse models, carrying conditionally either a tumor driving KRAS or an EGFR mutation (C) were used to study tumor growth in response to LSD1 inhibition using HCI-2509. Computer tomography showed less tumor formation after HCI-2509 treatment in both, the EGFR (D) or the KRAS (E) mutant model. HCI-2509-inhibited tumor development was associated with lower Ki67 proliferation rates (F) and changes in LSD1 protein levels as well as in alterations of the H3K4 methylation pattern (cf. Macheleidt et al. 2018)