LSD1 activates a lethal prostate cancer gene network independently of its demethylase function

Sehrawat, Archana; Gao, Lina; Wang, Yuliang; Bankhead, Armand; McWeeney, Shannon K.; King, Carly J.; Schwartzman, Jacob; Urrutia, Joshua A.; Bisson, William H.; Coleman, Daniel J.; Joshi, Sunil; Kim, Dae Hwan; Sampson, David A.; Weinmann, Sheila; Kallakury, Bhaskar; Berry, Deborah L.; Haque, Reina; Eeden, Stephen K. Van Den; Sharma, Sunil; Bearss, Jared; Beer, Tomasz M.; Thomas, George V.; Heiser, Laura M.; Alumkal, Joshi J.

doi:10.1073/pnas.1719168115

Cited by 182 publications

(214 citation statements)

References 47 publications

(76 reference statements)

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“…39 In line with this model, recent reports in prostate cancer cell lines described a scaffolding role for KDM1A, whereby catalytically inactive KDM1A was still able to establish the prostate cancer gene network and ensure survival of castration-resistant prostate cancer cell lines. 40 This was further confirmed with the tool compound SP2509, proposed as an allosteric inhibitor binding to the H3 pocket region of KDM1A, capable of inducing cell death in prostate cancer cell lines. Similarly, this could also explain the previously observed reversal of the EWS-FL1 signature effects with SP2509 in Ewing sarcoma cells.…”

Section: Global or Promoter-specific Accumulation Of Methylation Of H3k4mentioning

confidence: 68%

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Romo-Morales

Aładowicz

Blagg

et al. 2019

Pediatric Blood & Cancer

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Background Ewing sarcoma and desmoplastic small round cell tumors (DSRCT) are rare and clinically aggressive sarcomas usually characterized by oncogenic fusion proteins involving EWS. Emerging studies of Ewing sarcoma have demonstrated EWS‐FLI1‐driven chromatin remodeling as a key aspect of tumorigenicity. In particular, the lysine‐specific demethylase KDM1A/LSD1 is linked to transcriptional regulation of target genes orchestrated by the EWS portion of the fusion protein interacting with repressive chromatin‐remodeling complexes. Consistent with this model, depletion of KDM1A supports it is a molecular therapeutic target in Ewing sarcoma cells, but effective drugs need to be identified. Procedure A comprehensive phenotypic analysis of the effects of catalytic KDM1A inhibitors ORY‐1001 and GSK2879552, including clinically relevant doses, was carried out in 2D and 3D spheroid models of Ewing sarcoma and DSRCT. Results Catalytic inhibition of KDM1A did not affect cell viability in 2D and 3D assays and had no impact on invasion in a 3D assay. Conclusions Overall, evidence presented here does not support inhibition of KDM1A catalytic demethylase activity as an effective therapeutic strategy for Ewing sarcoma or DSRCT. However, roles of KDM1A beyond its demethylase activity should be considered for these sarcomas.

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Section: Global or Promoter-specific Accumulation Of Methylation Of H3k4mentioning

confidence: 68%

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Romo-Morales

Aładowicz

Blagg

et al. 2019

Pediatric Blood & Cancer

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“…Other coregulators of AR, such as lysine-specific histone demethylase 1A (LSD1), have been shown to have a reprogrammed activity in CRPCs, where it is also highly expressed (Liang et al 2017, Sehrawat et al 2018. Importantly, LSD1 has been shown to be one of the responsible factors for AR in castration-challenged PC cells (Cai et al 2011).…”

Section: The Androgen Receptor Drives Chromatin Relaxation As An Oncomentioning

confidence: 99%

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Braadland

Urbanucci

2019

Endocrine-Related Cancer

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Tumor evolution is based on the ability to constantly mutate and activate different pathways under the selective pressure of targeted therapies. Epigenetic alterations including those of the chromatin structure are associated with tumor initiation, progression and drug resistance. Many cancers, including prostate cancer, present enlarged nuclei, and chromatin appears altered and irregular. These phenotypic changes are likely to result from epigenetic dysregulation. High-throughput sequencing applied to bulk samples and now to single cells has made it possible to study these processes in unprecedented detail. It is therefore timely to review the impact of chromatin relaxation and increased DNA accessibility on prostate cancer growth and drug resistance, and their effects on gene expression. In particular, we focus on the contribution of chromatinassociated proteins such as the bromodomain-containing proteins to chromatin relaxation. We discuss the consequence of this for androgen receptor transcriptional activity and briefly summarize wider gain-of-function effects on other oncogenic transcription factors and implications for more effective prostate cancer treatment.

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“…Additionally, we observed that the half‐life of LSD1 is decreased from an initial 30 h to 21 h after HCI‐2509 treatment. This is in agreement with previous studies with respect to neuroblastoma and prostate cancer (Ambrosio et al ., ; Sehrawat et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

et al. 2018

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Lung adenocarcinoma (LUAD) is the most prevalent subtype of non‐small cell lung cancer. Despite the development of novel targeted and immune therapies, the 5‐year survival rate is still only 21%, indicating the need for more efficient treatment regimens. Lysine‐specific demethylase 1 (LSD1) is an epigenetic eraser that modifies histone 3 methylation status, and is highly overexpressed in LUAD. Using representative human cell culture systems and two autochthonous transgenic mouse models, we investigated inhibition of LSD1 as a novel therapeutic option for treating LUAD. The reversible LSD1 inhibitor HCI‐2509 significantly reduced cell growth with an IC 50 of 0.3–5 μm in vitro, which was linked to an enhancement of histone 3 lysine methylation. Most importantly, growth arrest, as well as inhibition of the invasion capacities, was independent of the underlying driver mutations. Subsequent expression profiling revealed that the cell cycle and replication machinery were prominently affected after LSD1 inhibition. In addition, our data provide evidence that LSD1 blockade significantly interferes with EGFR downstream signaling. Finally, our in vitro results were confirmed by preclinical therapeutic approaches, including the use of two autochthonous transgenic LUAD mouse models driven by either EGFR or KRAS mutations. 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. Hence, our findings provide substantial evidence indicating that tumor growth of LUAD can be markedly decreased by HCI‐2509 treatment, suggesting its use as a single agent maintenance therapy or combined therapeutical application in novel concerted drug approaches.

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LSD1 activates a lethal prostate cancer gene network independently of its demethylase function

Cited by 182 publications

References 47 publications

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

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