KDM1 Histone Lysine Demethylases as Targets for Treatments of Oncological and Neurodegenerative Disease

Maes, Tamara; Mascaró, Cristina; Ortega, Alberto; Lunardi, Serena; Ciceri, Filippo; Somervaille, Tim C. P.; Buesa, Carlos

doi:10.2217/epi.15.9

Cited by 67 publications

(51 citation statements)

References 114 publications

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“…LSD1 has been characterized as a potential oncogene and a therapeutic target in several cancer types (17)(18)(19). In acute myeloid leukemia (AML), LSD1 overexpression blocks differentiation and confers a poor prognosis (20,21).…”

Section: Introductionmentioning

confidence: 99%

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

Ahmed

Guo

et al. 2017

Cancer Research

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Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. .

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Section: Introductionmentioning

confidence: 99%

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

Ahmed

Guo

et al. 2017

Cancer Research

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“…To whom correspondence should be addressed. KDM1 (20,21) that removes methyl groups from mono-and dimethylated lysine 4 of histone H3 (22). The JARID1 (Jumonji, AT-rich interactive domain) family of histone lysine demethylases represents one such potential target.…”

mentioning

confidence: 99%

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Horton¹,

Engstrom²,

Zoeller³

et al. 2016

Journal of Biological Chemistry

104

165

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The KDM5/JARID1 family of Fe(II)-and ␣-ketoglutarate-dependent demethylases remove methyl groups from tri-and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC). Here we demonstrate that internal deletion of the ARID and PHD1 domains has a negligible effect on in vitro enzymatic kinetics of the KDM5 family of enzymes. We present a crystal structure of the linked JmjN-JmjC domain from KDM5A, which reveals that the linked domain fully reconstitutes the cofactor (metal ion and ␣-ketoglutarate) binding characteristics of other structurally characterized Jumonji domain demethylases. Docking studies with GSK-J1, a selective inhibitor of the KDM6/ KDM5 subfamilies, identify critical residues for binding of the inhibitor to the reconstituted KDM5 Jumonji domain. Further, we found that GSK-J1 inhibited the demethylase activity of KDM5C with 8.5-fold increased potency compared with that of KDM5B at 1 mM ␣-ketoglutarate. In contrast, JIB-04 (a paninhibitor of the Jumonji demethylase superfamily) had the opposite effect and was ϳ8-fold more potent against KDM5B than against KDM5C. Interestingly, the relative selectivity of JIB-04 toward KDM5B over KDM5C in vitro translates to a ϳ10 -50-fold greater growth-inhibitory activity against breast cancer cell lines. These data define the minimal requirements for enzymatic activity of the KDM5 family to be the linked JmjNJmjC domain coupled with the immediate C-terminal helical zinc-binding domain and provide structural characterization of the linked JmjN-JmjC domain for the KDM5 family, which should prove useful in the design of KDM5 demethylase inhibitors with improved potency and selectivity.

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“…Correspondingly, chemical inhibitors are under active development to intervene their enzymatic activities for cancer therapy. For instance, the KDM1A inhibitors are in Phase I study for treatment of acute leukemia and small cell lung cancer (Maes et al, 2015). Understanding the regulatory mechanism of KDMs would provide a better grip on the biological role of KDMs and improve pharmacological inhibition of their activities in disease states.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitors

Huang

et al. 2020

Preprint

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1 2 CTR9 is the scaffold subunit in Paf1c, a multifunctional complex regulating multiple steps 3 of RNA Pol II-mediated transcription. Using inducible and stable CTR9 knockdown breast 4 cancer cell lines, we discovered that the expression of a subset of KDMs, including 5 KDM6A and Jarid2, is strictly controlled by CTR9. Global analyses of histone modifications 6 revealed a significant increase of H3K27me3 upon loss of CTR9. Loss of CTR9 results in 7 a decrease of H3K4me3 and H3K36me3 in gene bodies, and elevated levels and genome-8 wide expansion of H3K27me3. Mechanistically, CTR9 depletion triggers a PRC2 subtype 9 switching from PRC2.2 to PRC2.1. As a consequence, CTR9 depletion generates 10 vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our 11 findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic 12 distribution, provide a unique mechanism of transition from transcriptionally active to 13 repressive chromatin states and sheds light on the biological functions of CTR9 in 14 development and cancer. 15 16 17 18 19 20 21 22 23 4 RESULTS 1 2 CTR9 regulates a subset of histone lysine demethylases (KDMs) in ER+ breast 3 cancer cells 4 Data mining of the CTR9-regulated transcriptome in CTR9 inducible knockdown (KD) 5 MCF7 cells (MCF7-tet-on-shCtr9) (Figure 1A) (Zeng and Xu, 2016) identified a subset of 6 KDM genes that mirrors the expression of CTR9, including KDM1A, KDM2B, KDM3B, 7KDM5B, KDM6A and JARID2. We found that these KDM genes were down-regulated 8 when CTR9 was knocked down by shRNA in MCF7 cells after a 7-day doxycycline (Dox) 9 treatment ( Figure 1B) regardless of whether 17β-estradiol (E2) was present or absent. 10RNAPII binding peaks at the transcription start site (TSS) of several KDM genes also 11 decreased in response to CTR9 depletion ( Figure S1A). We validated the transcriptome 12 array results by RT-qPCR. Figure 1C shows that silencing of CTR9 after a 7-day Dox 13 treatment reduced the total mRNA levels, and reduced the expression of ribosome-14 associated RNAs, which are indicative of actively transcribed mRNAs, of six KDMs. 15However, the mRNA levels of KDM4B and KDM6B did not significantly change. CTR9's 16 regulation of KDMs was also observed at the protein level. As shown in Figure 1D, the 17 protein levels of six KDMs significantly decreased in the total cell lysates and extracted 18 chromatin fractions. Consistent with their mRNA levels in response to CTR9 depletion, 19 KDM4B and KDM6B protein levels also remained unchanged. To exclude the possibility 20 that this observation was specific to MCF7, or due to off-target effects of anti-CTR9 shRNA, 21 we employed MCF7 cells as well as T47D cells, another well-established ERα+ breast 22 34 35

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KDM1 Histone Lysine Demethylases as Targets for Treatments of Oncological and Neurodegenerative Disease

Cited by 67 publications

References 114 publications

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

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

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitors

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