CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression

Hsu, Hung‐Chih; Liu, Yi-Shiuan; Tseng, Kai-Chi; Yang, Tsung‐Ming; Yeh, Chien-Yuh; You, Jeng-Fu; Hung, Hsin-Yuan; Chen, Shu‐Jen; Chen, Hua‐Chien

doi:10.1007/s00432-014-1782-4

Cited by 24 publications

(22 citation statements)

References 40 publications

(44 reference statements)

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“…To deconvolute whether we lose these cell populations or have a global decrease in transcript expression for these genes, we performed scRNA-seq on HT29 and H508 cells after LSD1 KD and integrated these samples into the previously analyzed empty vector (EV) controls using Seurat, as described in the Supplemental Methods. Consistent with reports of LSD1 overexpression in CRC (Hsu et al, 2015), LSD1 expression was elevated in our cell lines compared to the normal colon, which had expression levels similar to the HT29 and H508 LSD1 KD samples (Supplemental Figure 10D).…”

Section: Lsd1 Knockdown Results In Loss Of Secretory Cellssupporting

confidence: 91%

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

Miller

Policastro

Sriramkumar

et al. 2020

Preprint

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Despite the connection to distinct mucus-containing colorectal cancer (CRC) histological subtypes, the role of secretory cells, including goblet and enteroendocrine (EEC) cells, in CRC progression has been underexplored. Analysis of TCGA and single cell RNA sequencing data demonstrates that multiple secretory progenitor populations are enriched in BRAF-mutant CRC patient tumors and cell lines. Enrichment of EEC progenitors in BRAF-mutant CRC is maintained by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of EECs. Mechanistically, secretory cells and the factors they secrete, such as Trefoil factor 3, are shown to promote colony formation and activation of cell survival pathways in the entire cell population. We further identify LSD1 as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss reduces tumor growth and metastasis. This work establishes EEC progenitors, in addition to goblet cells, as targetable populations in BRAF-mutant CRC and identifies LSD1 as a therapeutic target in secretory lineage-containing CRC.

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Section: Lsd1 Knockdown Results In Loss Of Secretory Cellssupporting

confidence: 91%

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

Miller

Policastro

Sriramkumar

et al. 2020

Preprint

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“…A limited number of studies have been performed in other types of CSCs, they confirm, however, the link between LSD1 and cancer stemness. In colorectal carcinoma, there is a positive correlation between the immunohistochemical expression of LSD1 with LGR5, an established stem cell marker of this tissue [112]. Stem cell derived tumors, such as embryonic carcinomas, teratocarcinomas and seminomas, are exceptionally vulnerable to LSD1 inhibition with severe growth impairment [113,114].…”

Section: Lsd1 In Other Types Of Cscsmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1’s role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives.

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“…KDM1A plays a role in activating the Wnt/β-catenin signaling pathway, but, at the same time, downregulates the signaling pathway antagonistic to the colorectal cancer-related gene dickkopf-1 ( DKK1 ) [ 141 ]. Moreover, increased expression of KDM1A is also associated with the expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a well-known colorectal cancer stem cell marker [ 142 ]. The inhibition of KDM1A attenuates Wnt/β-catenin signaling and diminishes colorectal cancer progression by downregulating the expression of LGR5 [ 142 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, increased expression of KDM1A is also associated with the expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a well-known colorectal cancer stem cell marker [ 142 ]. The inhibition of KDM1A attenuates Wnt/β-catenin signaling and diminishes colorectal cancer progression by downregulating the expression of LGR5 [ 142 ].…”

Section: Introductionmentioning

confidence: 99%

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

Ismail

Lee

Kim

et al. 2018

Epigenetics & Chromatin

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The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs.

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CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression

Cited by 24 publications

References 40 publications

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

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