Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation

Rummukainen, Petri; Tarkkonen, Kati; Dudakovic, Amel; Al-Majidi, Rana; Nieminen-Pihala, Vappu; Valensisi, Cristina; Hawkins, R. David; Wijnen, André J. van; Kiviranta, Riku

doi:10.1371/journal.pone.0265027

Cited by 16 publications

(15 citation statements)

References 95 publications

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“…In other complexes, such as the co-repressor of repressor element-1 silencing transcription factor (CoREST) complex, LSD1 targets H3K4me for demethylation ( 22 ). Different LSD1 complexes have been identified in different cell types and different contexts ( 25 – 27 ). Here we’ll briefly discuss the more commonly observed LSD1 complex composition, with a focus on those complexes likely to be important in sarcoma.…”

Section: Discovery Of Lsd1mentioning

confidence: 99%

“…In osteogenesis, the work that has been done demonstrates opposing functions of LSD1 in regulating bone formation. LSD1 is highly expressed in osteoblasts and is recruited to specific DNA motifs at osteogenic promoters to remove repressive histone methylation marks ( 25 ). LSD1 activity thus induces differentiation of osteoblasts to promote bone formation and in vitro knockdown of LSD1 in mouse mesenchymal cells impaired normal bone formation ( 25 ).…”

Section: Lsd1 In Mesenchymal Differentiation and Developmentmentioning

confidence: 99%

“…LSD1 is highly expressed in osteoblasts and is recruited to specific DNA motifs at osteogenic promoters to remove repressive histone methylation marks ( 25 ). LSD1 activity thus induces differentiation of osteoblasts to promote bone formation and in vitro knockdown of LSD1 in mouse mesenchymal cells impaired normal bone formation ( 25 ). Similarly, in fracture repair LSD1 represses retinoic acid signaling in order to allow cartilaginous callus formation for bone endochondral ossification ( 51 ).…”

Section: Lsd1 In Mesenchymal Differentiation and Developmentmentioning

confidence: 99%

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Lysine specific demethylase 1 is a molecular driver and therapeutic target in sarcoma

Dreher

Theisen

2023

Front. Oncol.

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Sarcomas are a diverse group of tumors with numerous oncogenic drivers, and display varied clinical behaviors and prognoses. This complexity makes diagnosis and the development of new and effective treatments challenging. An incomplete understanding of both cell of origin and the biological drivers of sarcomas complicates efforts to develop clinically relevant model systems and find new molecular targets. Notably, the histone lysine specific demethylase 1 (LSD1) is overexpressed in a number of different sarcomas and is a potential therapeutic target in these malignancies. With the ability to modify histone marks, LSD1 is a key player in many protein complexes that epigenetically regulate gene expression. It is a largely context dependent enzyme, having vastly different and often opposing roles depending on the cellular environment and which interaction partners are involved. LSD1 has been implicated in the development of many different types of cancer, but its role in bone and soft tissue sarcomas remains poorly understood. In this review, we compiled what is known about the LSD1 function in various sarcomas, to determine where knowledge is lacking and to find what theme emerge to characterize how LSD1 is a key molecular driver in bone and soft tissue sarcoma. We further discuss the current clinical landscape for the development of LSD1 inhibitors and where sarcomas have been included in early clinical trials.

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Section: Discovery Of Lsd1mentioning

confidence: 99%

Section: Lsd1 In Mesenchymal Differentiation and Developmentmentioning

confidence: 99%

Section: Lsd1 In Mesenchymal Differentiation and Developmentmentioning

confidence: 99%

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Lysine specific demethylase 1 is a molecular driver and therapeutic target in sarcoma

Dreher

Theisen

2023

Front. Oncol.

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“…Inhibition of LSD1 promotes osteoblast differentiation and bone formation in human mesenchymal stem cells (hMSCs) [ 28 ]. Interestingly, Petri et al reported that the suppression of the LSD1 activity inhibits osteoblast differentiation [ 29 ]. A recent study indicated that the deletion of LSD1 in female mice increases bone mass [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Crucial Role of Lysine-Specific Histone Demethylase 1 in RANKL-Mediated Osteoclast Differentiation

Ding

Chen

Cho

et al. 2023

IJMS

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Epigenetic regulators are involved in osteoclast differentiation. This study proposes that the inhibitors of epigenetic regulators could be effective in the treatment of osteoporosis. This study identified GSK2879552, a lysine-specific histone demethylase 1 (LSD1) inhibitor, as a candidate for the treatment of osteoporosis from epigenetic modulator inhibitors. We investigate the function of LSD1 during RANKL-induced osteoclast formation. LSD1 small-molecule inhibitors effectively inhibit the RANKL-induced osteoclast differentiation in a dose-dependent manner. LSD1 gene knockout in macrophage cell line Raw 264.7 also inhibits RANKL-mediated osteoclastogenesis. LSD1-inhibitor-treated primary macrophage cells and LSD1 gene knockout Raw 264.7 cells failed to show actin ring formation. LSD1 inhibitors prevent the expression of RANKL-induced osteoclast-specific genes. They also downregulated the protein expression of osteoclast-related markers in osteoclastogeneses, such as Cathepsin K, c-Src, and NFATc1. Although LSD1 inhibitors were shown to reduce the in vitro demethylation activity of LSD1, they did not modulate the methylation of Histone 3 K4 and K9 during osteoclastogenesis. The ovariectomy (OVX)-induced osteoporosis model revealed that GSK2879552 slightly restores OVX-induced cortical bone loss. LSD1 can be employed as a positive regulator to promote osteoclast formation. Hence, inhibition of LSD1 activities is a potential target for preventing bone diseases characterized by excessive osteoclast activities.

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“…Lysine (K)-specific demethylase 1 A (KDM1A, also refers to as LSD1) is a regulatory protein of methylation, which is one type of histone modification (Kim et al 2021). A previous publication reported that KDM1A used flavin adenine dinucleotide/dependent mechanism to demethylate H3K9me3 and regulated genes in MSCs (Rummukainen et al 2022). KDM1A was also shown to have a complex role in different stages of osteogenic differentiation (Wang et al 2018;Lv et al 2016).…”

Section: Introductionmentioning

confidence: 99%

CircRNA AFF4 induced by KDM1A promotes osteogenic differentiation through FNDC5/Irisin pathway

Liu

Chen

Zhong

et al. 2022

Mol Med

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Background Circular RNA (circ) AFF4 was documented to regulate osteogenesis but the underlying mechanism remains to be elucidated. The preliminary study showed that circ_AFF4 may promote osteogenesis via FNDC5/Irisin. Furthermore, the online prediction tool indicated the interaction of circ_AFF4, insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3), FNDC5 and lysine (K)-specific demethylase 1 A (KDM1A). Therefore, this study aims to elucidate the relationships of KDM1A, circ_AFF4, IGF2BP3 and FNDC5/Irisin during osteogenesis. Methods The alkaline phosphatase (ALP) activities and osteogenic-related factors were determined using ALP and alizarin red S (ARS) staining, real-time quantitative PCR(RT-qPCR) and western blot. Immunoprecipitation (RIP), pull-down assay and fluorescence in situ hybridization (FISH) were used to examine the interactions among circ_AFF4/IGF2BP3/FNDC5. A mouse in vivo model was utilized to further confirm the regulatory effect on bone formation. Results Circ_AFF4 and KDM1A expression levels were increased during osteoinduction of BM-MSCs. Knockdown of circ_AFF4 and KDM1A significantly suppressed BM-MSC osteogenesis. We also proved that KDM1A directly bound to circ_AFF4 and FNDC5 promoter and induced circ_AFF4 and FNDC5 expression. Furthermore, circ_AFF4 enhanced the stability of FNDC5 by generating a circ_AFF4, IGF2BP3 and FNDC5 RNA-protein complex, and thereby induced Irisin and osteogenesis. The in vitro data was confirmed with in vivo model. Conclusion These findings elucidate that KDM1A induces circ_AFF4, which promotes promote osteogenesis via IGF2BP3. This study indicates that circ_AFF4 may potentially represent a critical therapeutic target for the diseases.

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Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation

Cited by 16 publications

References 95 publications

Lysine specific demethylase 1 is a molecular driver and therapeutic target in sarcoma

Lysine specific demethylase 1 is a molecular driver and therapeutic target in sarcoma

Crucial Role of Lysine-Specific Histone Demethylase 1 in RANKL-Mediated Osteoclast Differentiation

CircRNA AFF4 induced by KDM1A promotes osteogenic differentiation through FNDC5/Irisin pathway

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