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. 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. Our recent studies proved that LSD1 overexpression is associated with NSCLC malignancy (Lim et al. 2017). 

LSD1 inhibitors as novel therapeutic option

Due to the tumor driving potential, novel efficient LSD1 inhibitors are under development. The recently identified inhibitor HCI-2509 is a very potent LSD1 inhibitor, which reversibly binds to LSD1, but also disables its solubility and blocks its interactions within the chromatin remodeling complex e.g. CoREST complex.

In various NSCLC cell lines, HCI-2509 significantly reduced cell growth with an IC50 of 0.3 to 5 µM (Macheleidt et al. 2018). Most importantly, HCI-2509 mediated 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 1 A,B). These in vitro findings were confirmed by preclinical therapeutic approaches including two transgenic NSCLC mouse models driven by either an activating EGFR or KRAS mutation (Figure 1 C-G) (Macheleidt et al. 2018). 

Hence, our findings suggest LSD1 inhibition as a therapeutic target in novel treatment strategies of combinatorial therapy. 

LSD1 inhibition leads to cell growth arrest by repression of the PLK1 pathway

Expression profiling followed by functional classification and pathway analysis indicated prominent repression of proliferation-associated signaling upon LSD1 inhibition. In particular, the polo-like kinase 1 (PLK1) pathway was downregulated in response to LSD1 inhibition (Figure 2). Notably, using TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. This LSD1/PLK1 linkage was confirmed by immunohistochemical analysis of NSCLC tumor samples (Figure 2D, E), demonstrating the clinical relevance of the LSD1 /PLK1 axis (Dalvi et al. 2019). 

Importantly, whereas the PLK1 pathway is downregulated, the tumor suppressor CDKN1A is upregulated upon LSD1 inhibition. Chromatin immunoprecipation (ChIP) followed by whole genome sequencing or qPCR demonstrated that both are direct targets of LSD1 transcriptional gene regulation (Figure 3). 


Nuclear encoded mitochondrial (mt) proteins are markedly LSD1 regulated, leading to impaired mt-respiration and ATP production as well as to immense changes in metabolism. The cancer associated metabolic alterations upon LSD1 inhibition will be subject of further studies.

Selected publications (2017-2019)

1. Dalvi P.S., Macheleidt I.F., Lim S.Y., 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. 17(6), 1326-1337. 

2. Mariappan A, Soni K, Macheleidt I, et al, Odenthal M, Büttner R, et  al., and Gopalakrishnan J. (2019) Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J. 38(2).

3. Macheleidt I.F., Dalvi P.S., Lim SY., Meemboor S.,et al. Buettner R., and Odenthal M. (2018) Growth arrest of non-small cell lung cancer shown by preclinical studies using the LSD1 inhibitor HCI-2509. Molecular Oncology 12(11), 1965-1979. 

4. Grasse S, Lienhard M, et al. Odenthal M, Büttner R, et al., and Schweiger MR. (2018) Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Med. J 10(1):55.

5. Lim S.Y., Macheleidt, I., Dalvi P., et al. 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.

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

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

8. Amer W, Toth C, Vassella E, et al.  Buettner R, Scheel A, Schaefer SC, and 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.

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

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. Priya Dalvi (PostDoc) 
Dr. Iris F. Macheleidt (PostDoc)
Marcel Schmiel (Medical student)
Miriam Weiß (Medical student)
Jie Wang (PhD student)
Hannah Eischeidt-Scholz (technician)

Figure 1

CMMC Research Odenthal
Figure 1: Tumor cell growth arrest upon LSD1 inhibition
Cell growth was inhibited in different NSCLC cell lines by the LSD1 inhibitor HCI-2509 (A) as a result of 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 and the KRAS mutant model (D). HCI-2509-inhibited tumor development (E) was associated with lower Ki67 proliferation rates (F) and in alterations of the H3K4 / H3K9 methylation (Macheleidt et al. 2018).

Figure 2

CMMC Research Odenthal
Figure 2: Gene expression profiling of PC9 lung cancer cells proved changes in expression of cell cycle associated genes upon LSD1 inhibition. Especially, PLK1 and genes of the PLK1 pathway were prominently repressed after LSD1 inhibition (A, B, C). TCGA transcriptomic data sets (D) and immunohistology studies on NSCLC tissue microarrays (E) proved a significant correlation of LSD1 and PLK1 (Dalvi et al. 2019).

Figure 3

CMMC Research Odenthal
Figure 3: PLK1 and CDKN1A are direct targets of LSD1 regulation. ChIP followed by ultra-deep DNA sequencing demonstrated LSD1 interaction with the PLK1 (A) and the CDKN1A promoter (B) (upper panel). LSD1 interaction was decreased after anti-LSD1 siRNA treatments proven by ChIP-qPCR analysis (lower panel).