LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Lv, Yi; Ahmed, Musaddeque; Guo, Haiyang; Soares, Fraser; Hua, Junjie; Gao, Shuai; Lu, Catherine; Poon, Christine; Han, Wanting; Langstein, Jens; Ekram, Muhammad B.; Li, Brian; Davicioni, Elai; Takhar, Mandeep; Erho, Nicholas; Karnes, R. Jeffrey; Chadwick, Dianne; Kwast, Theodorus van der; Boutros, Paul C.; Arrowsmith, C.H.; Feng, Felix Y.; Joshua, Anthony M.; Zoubeidi, Amina; Cai, Changmeng; He, Housheng Hansen

doi:10.1158/0008-5472.can-17-0496

Cited by 80 publications

(66 citation statements)

References 50 publications

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“…Microarray profiling revealed that LSD1 inhibition led to differential expression of genes, and further comprehensive analysis showed a significant downregulation of several genes associated with cell-cycle progression and therefore leading to a cell-cycle arrest. The gene expression profiles are consistent with the work of Liang and colleagues, who also showed deregulation of cell-cycle-related genes upon LSD1 inhibition (35). Interestingly, classification of the differentially expressed genes identified the G 2 -M DNA damage checkpoint regulation pathway to be significantly activated, and the mitotic roles of PLK pathway to be significantly downregulated after LSD1 inhibition.…”

Section: Discussionsupporting

confidence: 87%

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

Dalvi

Macheleidt

Lim

et al. 2019

Molecular Cancer Research

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Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma, which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the lung adenocarcinoma cell line PC9, using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell-cycle arrest of the tumor cells in the G 2-M-phase. Expression profiling followed by functional classification and pathway analysis indicated prominent repression of the polo-like kinase 1 (PLK1) pathway upon LSD1 inhibition. In contrast, transient overexpression of exogenous PLK1 plasmid rescued the LSD1 inhibition-mediated downregulation of PLK1 pathway genes. Mechanistically, LSD1 directly regulates expression of PLK1 by binding to its promoter region that subsequently affects expression of its downstream target genes. Notably, using lung adenocarcinoma TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. Furthermore, the LSD1/PLK1 linkage was confirmed by IHC analysis in a clinical lung adenocarcinoma cohort (n ¼ 43). Conclusively, this is the first study showing a direct transcriptional link between LSD1 and PLK1. Implications: These findings point to a role of LSD1 in regulating PLK1 and thus efficient G 2-M-transitionmediating proliferation of tumor cells and suggest targeting the LSD1/PLK1 axis as a novel therapeutic approach for lung adenocarcinoma treatment.

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Section: Discussionsupporting

confidence: 87%

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

Dalvi

Macheleidt

Lim

et al. 2019

Molecular Cancer Research

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“…36 LSD1 was found to promote CRPC also through epigenetic programming to induce CENPE, a centromere-binding protein and mitotic kinesin, expression. 37 LSD1 is significantly upregulated in CRPC, which may suggest serve as a predictive biomarker of aggressive prostate cancer. Targeting LSD1 in conjunction with AR antagonists may also be a promising therapeutic approach to treat CRPC.…”

Section: Histone Modificationsmentioning

confidence: 97%

Epigenetic modulations and lineage plasticity in advanced prostate cancer

et al. 2020

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Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.

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“…Lysine-specific demethylase 1 (LSD1) functions as a transcriptional repressor of AR-regulated enhancers through H3K4 demethylation and as an ARlinked coactivator through interaction with CoREST and histone H3 Thr6 phosphorylation (H3T6ph) (Cai et al 2011(Cai et al , 2014. LSD1 also promotes prostate cancer cell survival through activation of a gene network associated with a lethal prostate cancer independent of its demethylase function (Sehrawat et al 2018) and promotes CRPC through epigenetic programming to induce CENPE expression (Liang et al 2017).…”

Section: Epigenetic Deregulationmentioning

confidence: 99%

Genetics and biology of prostate cancer

et al. 2018

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Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels. Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological advances focused on disease detection and management. These advances, along with an improved understanding of the adaptive responses to conventional cancer therapies, anti-androgen therapy, and immunotherapy, are catalyzing development of more effective therapeutic strategies for advanced disease. In particular, knowledge of the heterotypic interactions between and coevolution of cancer and host cells in the tumor microenvironment has illuminated novel therapeutic combinations with a strong potential for more durable therapeutic responses and eventual cures for advanced disease. Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.

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LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Cited by 80 publications

References 50 publications

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

Epigenetic modulations and lineage plasticity in advanced prostate cancer

Genetics and biology of prostate cancer

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