Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1

Cao, Yang; Tang, Lingyi; Du, Kang; Paraiso, Kitt D.; Sun, Qiong; Liu, Zhengxia; Ye, Xiaolong; Fang, Yuan; Chen, Hank; Chen, Yumay; Wang, Xiaorong; Yu, Clinton; Blitz, Ira L.; Huang, Lan; Cheng, Haibo; Lü, Xiang; Cho, Ken W.Y.; Seldin, Marcus M.; Fang, Zheng; Yang, Qin

doi:10.1172/jci.insight.147692

Cited by 10 publications

(5 citation statements)

References 92 publications

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“…Targeting of KDM1A activity has become a promising cancer therapy, and numerous KDM1A inhibitors have been tested in clinical trials ( 40 ). In addition, it has been reported that deficiency of Kdm1a in high-fat diet–fed mice ameliorated NASH and obesity ( 41 ). Our present study supports the KDM1A-SIKE axis as a promising avenue for anti-NASH drug development.…”

Section: Discussionmentioning

confidence: 99%

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression

Bai,

Qu,

Cheng

et al. 2024

Sci. Transl. Med.

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Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε ( SIKE ) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-β–activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.

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Section: Discussionmentioning

confidence: 99%

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression

Bai,

Qu,

Cheng

et al. 2024

Sci. Transl. Med.

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“…Cao et al [93] reported that LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes [93]. Experiments of genome-wide binding and transcriptome analyses demonstrated that LSD1 directly stimulated the expression of genes involved in OXPHOS in cooperation with the nuclear respiratory factor 1 (Nrf1) [94].…”

Section: Discussionmentioning

confidence: 99%

Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules

Bibbò,

Asadzadeh,

Boccia

et al. 2024

IJMS

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Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial–mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.

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“…The highly conserved SWIRM domain of LSD1 interacts with SIRT to form a functional complex, which mediates the activity of SIRT1. The interaction between SIRT1 and LSD1 plays a conserved and cooperative role in H3K4 demethylation to inhibit Notch signalling-mediated gene transcription ( Cao et al, 2021 ). SIRT1 and LSD1 are aberrantly expressed in cancers and play an antagonistic role in DNA repair and mutation acquisition ( Boila and Sengupta, 2020 ; Wang et al, 2020 ).…”

Section: Primary Targets or Signalling Pathways Mediated By Lsd1mentioning

confidence: 99%

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

Yang

Zang

et al. 2022

Front. Pharmacol.

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Epigenetics has emerged as a prime focus area in the field of cancer research. Lysine-specific demethylase 1A (LSD1), the first discovered histone demethylase, is mainly responsible for catalysing demethylation of histone 3 lysine 4 (H3K4) and H3K9 to activate or inhibit gene transcription. LSD1 is abnormally expressed in various cancers and participates in cancer proliferation, apoptosis, metastasis, invasion, drug resistance and other processes by interacting with regulatory factors. Therefore, it may serve as a potential therapeutic target for cancer. This review summarises the major oncogenic mechanisms mediated by LSD1 and provides a reference for developing novel and efficient anticancer strategies targeting LSD1.

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Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1

Cited by 10 publications

References 92 publications

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression

Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

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