KDM1 is a novel therapeutic target for the treatment of gliomas

Sareddy, Gangadhara R.; Nair, Binoj C.; Krishnan, Samaya K.; Gonugunta, Vijay K.; Zhang, Quan Guang; Suzuki, Takayoshi; Miyata, Naoki; Brenner, Andrew; Brann, Darrell W.; Vadlamudi, Ratna K.

doi:10.18632/oncotarget.725

Cited by 53 publications

(55 citation statements)

References 33 publications

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“…TUNEL analysis was done by using the In situ Cell Death Detection Kit (Roche, Indianapolis, IN) as per the manufacturer’s protocol. Five randomly selected microscopic fields in each group were used to calculate the relative ratio of TUNEL-positive cells (37). …”

Section: Methodsmentioning

confidence: 99%

Inhibition of mTOR Signaling Reduces PELP1-Mediated Tumor Growth and Therapy Resistance

Gonugunta

Sareddy

Krishnan

et al. 2014

Molecular Cancer Therapeutics

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Proline, Glutamic acid- and Leucine-rich Protein 1 (PELP1) is a proto-oncogene that modulates estrogen receptor (ER) signaling. PELP1 expression is upregulated in breast cancer, contributes to therapy resistance, and is a prognostic marker of poor survival. In a subset of breast tumors, PELP1 is predominantly localized in the cytoplasm and PELP1 participates in extranuclear signaling by facilitating ER interactions with Src and PI3 kinases. However, the mechanism by which PELP1 extranuclear actions contributes to cancer progression and therapy resistance remains unclear. In this study, we discovered that PELP1 crosstalked with the serine/threonine protein kinase mammalian target of rapamycin (mTOR) axis and modulated mTOR signaling. PELP1 knockdown significantly reduced the activation of mTOR downstream signaling components. Conversely, PELP1 overexpression excessively activated mTOR signaling components. We detected the presence of the mTOR signaling complex proteins in PELP1 immunoprecipitates. mTOR targeting drugs (Rapamycin or AZD8055) significantly reduced proliferation of PELP1 over expressed breast cancer cells both in vitro and in vivo xenograft tumor models. MCF7 cells that uniquely retain PELP1 in the cytoplasm showed resistance to hormonal therapy and mTOR inhibitors sensitized PELP1-cyto cells to hormonal therapy in xenograft assays. Notably, IHC studies using xenograft tumors derived from PELP1 overexpression model cells showed increased mTOR signaling and inhibition of mTOR rendered PELP1 driven tumors to be highly sensitive to therapeutic inhibition. Collectively, our data identified the PELP1-mTOR axis as a novel component of PELP1 oncogenic functions and suggest that mTOR inhibitor(s) will be effective chemotherapeutic agents for downregulating PELP1 oncogenic functions.

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Section: Methodsmentioning

confidence: 99%

Inhibition of mTOR Signaling Reduces PELP1-Mediated Tumor Growth and Therapy Resistance

Gonugunta

Sareddy

Krishnan

et al. 2014

Molecular Cancer Therapeutics

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“…20 KDM1A overexpression has been associated with various cancers including neuroblastoma, 24 colon cancer, 25 breast cancer, 26 ovarian cancer, 27 bladder cancer, 28 prostate cancer, 29 hepatocellular cancer 27,30 and glioma. 31 Recent studies demonstrated that KDM1A is essential to maintain the undifferentiated state of human embryonic stem cells 32 and regulates neural stem cell proliferation and differentiation. 33 KDM1A is essential for the oncogenic potential of MLL-AF9 leukemia stem cells 34 and its inhibition resulted in selective inhibition of pluripotent stem cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…We recently developed a novel KDM1A-specific inhibitor NCL-1 (N-[(1S)-3-[3-(trans-2-Aminocyclo-propyl)phenoxy]-1-(benzylcarbamoyl)propyl] benzamide) 37,38 that has potent inhibitory activity on various cancer cells. 31,38,39 Further, we developed another potent KDM1A inhibitor called NCD-38 (2-(N-4-phenylbenzenecarbonyl)amino-6-(trans-2-phenyl-cyclopropane-1-amino-N-(3-chlorobenzyl)hexaneamide trifluoroacetate) based on a novel concept of direct delivery of phenylcyclopropylamine to the KDM1A active site. 40 Here, we describe the therapeutic utility of two novel KDM1A inhibitors NCL-1 and NCD-38 on GSCs using in vitro and in vivo models.…”

Section: Introductionmentioning

confidence: 99%

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

et al. 2016

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Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs.

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“…The histone demethylase KDM1 was overexpressed in gliomas and its expression positively correlated with histological malignancy. Patient-derived primary GBM cells expressed high levels of KDM1 and pharmacological inhibition of KDM1 decreased their proliferation, reduced the expression of stemness markers CD133 and nestin in GBM cells and significantly reduced glioma growth in a murine xenograft model [43]. Moreover, inhibition of KDM1 sensitizes GBM cells to HDAC inhibitors (HDACi) [50].…”

Section: Misregulation Of Histone-modifying Enzymes In Gliomasmentioning

confidence: 99%

“…H3S10ph AURKB Increased activity [27] H3K27me2,3 EZH2 Overexpression [33][34][35][36][37][38] H3Y41ph JAK2 Increased activity [27] H3K9me3 KMT1E (SETDB1) Overexpression [39] H3K36me3 KMT3A (SETD2) Mutation [40] H3K4me1 KMT7 (SETD7) Mutation [28] H3T6ph PKCβ Increased activity [27] H3T11ph PKM2 Overexpression [41] H4R3me2 PRMT1 Overexpression [42] H3K9me3 SUV39H Overexpression [39] Erasers Pan-histone acetylation HDAC2 Mutation [28] Pan-histone acetylation HDAC4 Downregulation [32] Pan-histone acetylation HDAC5 Downregulation [32] Pan-histone acetylation HDAC6 Downregulation [32] Pan-histone acetylation HDAC7 Downregulation [32] Pan-histone acetylation HDAC9 Downregulation Mutation [32] [ 28] pan-histone acetylation HDAC11 Downregulation [32] H3K4me1,2; H3K9me1,2 KDM1 (LSD1) Overexpression [43] H3K9me1,2 KDM3A (JMJD1A) Mutation [28] H3K9me1,2 KDM3B (JMJD1B) Mutation [28] H3K4me1,2,3 KDM5B (JARID1B) Overexpression [44] H3K27me3 KDM6B (JMJD3) Overexpression [45] Readers…”

Section: Writersmentioning

confidence: 99%

Deregulation of Histone-Modifying Enzymes and Chromatin Structure Modifiers Contributes to Glioma Development

Maleszewska

Kamińska

2015

Future Oncol.

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The epigenetic landscape is deregulated in cancer due to aberrant activation or inactivation of enzymes maintaining and modifying the epigenome. Histone modifications and global aberrations at the histone level may result in distorted patterns of gene expression, and malfunction of proteins that regulate chromatin modification and remodeling. Recent whole genome studies demonstrated that histones and chaperone proteins harbor mutations that may result in gross alterations of the epigenome leading to genome instability. Glioma development is a multistep process, involving genetic and epigenetic alterations. This review summarizes newly identified mechanisms affecting expression/functions of histone-modifying enzymes and chromatin modifiers in gliomas. We discuss recent approaches to overcome epigenetic alterations with histone-modifying enzyme inhibitors and their prospects for glioma therapy.

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KDM1 is a novel therapeutic target for the treatment of gliomas

Cited by 53 publications

References 33 publications

Inhibition of mTOR Signaling Reduces PELP1-Mediated Tumor Growth and Therapy Resistance

Inhibition of mTOR Signaling Reduces PELP1-Mediated Tumor Growth and Therapy Resistance

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

Deregulation of Histone-Modifying Enzymes and Chromatin Structure Modifiers Contributes to Glioma Development

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