Review
Chemistry, Medicinal
Yihui Song, Huiqing Zhang, Xiaoke Yang, Yuting Shi, Bin Yu
Summary: Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising epigenetic target for disease treatment. This review provides an update on LSD1 inhibitors, including natural products, synthetic compounds, and cyclic peptides reported in 2021. The design strategies, structure-activity relationships, binding model analysis, and modes of action are discussed. Highlights include the repurposing of FDA-approved drugs as reversible LSD1 inhibitors, the identification of clinical candidates for neuro-developmental disorders, and the enhanced anti-cancer effects of dual inhibitors targeting both LSD1 and HDAC6 or tubulin.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Hideaki Niwa, Chiduru Watanabe, Shin Sato, Toshiyuki Harada, Hisami Watanabe, Ryo Tabusa, Shunsuke Fukasawa, Ayane Shiobara, Tomoko Hashimoto, Osamu Ohno, Kana Nakamura, Keiko Tsuganezawa, Akiko Tanaka, Mikako Shirouzu, Teruki Honma, Kenji Matsuno, Takashi Umehra
Summary: In this study, a total of 65 cis- and trans-PCPA derivatives were synthesized and evaluated for their inhibitory activity against LSD1 and LSD2. One derivative, 7c, showed high inhibitory activity against both LSD1 and LSD2, and increased the level of dimethylated histone H3 at K4 in cells. Additionally, a machine learning-based regression model was constructed to accurately predict LSD1 inhibitory activity.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Hideaki Niwa, Chiduru Watanabe, Shin Sato, Toshiyuki Harada, Hisami Watanabe, Ryo Tabusa, Shunsuke Fukasawa, Ayane Shiobara, Tomoko Hashimoto, Osamu Ohno, Kana Nakamura, Keiko Tsuganezawa, Akiko Tanaka, Mikako Shirouzu, Teruki Honma, Kenji Matsuno, Takashi Umehara
Summary: In this study, we synthesized and evaluated multiple cis- and trans-PCPA derivatives for their inhibitory activity against LSD1 and LSD2. A derivative named 7c showed high inhibitory activity against both LSD1 and LSD2, and increased a significant histone modification in cells. Furthermore, a regression model based on machine learning was constructed and demonstrated good prediction accuracy for LSD1 inhibitory activity.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Endocrinology & Metabolism
Lindsay Moritz, Saher Sue Hammoud
Summary: This article explores the molecular mechanisms underlying male fertility and the process of chromatin remodeling. It points out the current gaps in understanding of the chromatin remodeling process and suggests future research directions to enhance our knowledge of the histone-to-protamine exchange and the etiology of idiopathic male infertility.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Plant Sciences
Laura Poza-Viejo, Miriam Paya-Milans, Patxi San Martin-Uriz, Laura Castro-Labrador, David Lara-Astiaso, Mark D. Wilkinson, Manuel Pineiro, Jose A. Jarillo, Pedro Crevillen
Summary: Epigenetic regulation is crucial for optimal development and maintenance of gene expression profiles. This study uncovers the epigenetic mechanisms involved in flowering time regulation in Brassica rapa, shedding light on the conserved and distinct regulatory mechanisms between model and crop species.
PLANT CELL AND ENVIRONMENT
(2022)
Article
Cell Biology
Baoyu Chen, Yuwen Zhu, Junliang Chen, Yifei Feng, Yong Xu
Summary: This study reveals that differential TCL expression in malignant colorectal cancer cells is associated with histone H3K9 methylation, and the lysine demethylase KDM4B is essential for TCL transcription. KDM4B interacts with the transcription factor ERG1 to activate TCL transcription by facilitating the assembly of pre-initiation complex on the TCL promoter, ultimately influencing migration and invasion of CRC cells. Additionally, upregulation of KDM4B in advanced stage CRC specimens suggests it may serve as a potential therapeutic target for CRC intervention.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Yu Li, Yuanyuan Zhao, Xiaona Li, Liuqun Zhai, Hua Zheng, Ying Yan, Qiang Fu, Jinlian Ma, Haier Fu, Zhenqiang Zhang, Zhonghua Li
Summary: Alzheimer's disease is a common neurodegenerative disease with no cure. Lysine-specific demethylase 1 (LSD1) plays an important role in the pathogenesis of AD and has potential therapeutic benefits for treatment.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell Biology
Saikat Bhattacharya, Divya Reddy, Ning Zhang, Hua Li, Jerry L. L. Workman
Summary: The methyltransferase SETD2 plays a crucial role in regulating transcription, splicing, and other processes through the deposition of the H3K36me3 histone mark. Its stability is controlled by proteasome-mediated degradation to maintain low levels. Excessive SETD2 leads to upregulation of cell cycle-associated pathways, resulting in increased cell proliferation and migration.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Oncology
Md Sahab Uddin, Abdullah Al Mamun, Badrah S. Alghamdi, Devesh Tewari, Philippe Jeandet, Md Shahid Sarwar, Ghulam Md Ashraf
Summary: Research has shown that glioma progression is closely linked to different types of epigenetic phenomena, such as chromatin modifications, DNA methylation, chromatin remodeling, and aberrant microRNA. Targeting the genes and proteins that control these alterations can be an effective way to treat GBM. Treatment approaches include histone deacetylase inhibitors and DNA methyltransferase inhibitors.
SEMINARS IN CANCER BIOLOGY
(2022)
Article
Cell Biology
Ziyu Zhang, Baoyu Chen, Yuwen Zhu, Tianyi Zhang, Yibiao Yuan, Xiaoling Zhang, Yong Xu
Summary: TGF-beta regulates the transcription of the prometastatic small GTPase RHOJ by activating MKL1 and recruiting the H3K9/H3K27 dual demethylase KDM7A. KDM7A can be used to predict prognosis in breast cancer patients and its knockdown attenuates migration, invasion, growth, and metastasis of breast cancer cells. KDM7A is a direct transcriptional target of TGF-beta signaling, and small-molecule inhibitors of KDM7A may provide therapeutic solutions for malignant breast cancers.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Oncology
Jayden Sterling, Sharleen V. Menezes, Ramzi H. Abbassi, Lenka Munoz
Summary: Histone lysine demethylases (KDMs) are enzymes that remove methylation marks on lysines in nucleosomes' histone tails, regulating gene transcription and playing important roles in cancer development. KDMs can have activating or repressing effects on gene transcription, regulating the expression of oncogenes and tumor suppressors.
INTERNATIONAL JOURNAL OF CANCER
(2021)
Review
Oncology
Chunyan Hua, Jiaqing Chen, Shuting Li, Jianan Zhou, Jiahong Fu, Weijian Sun, Wenqian Wang
Summary: The review discusses the application of KDM6 demethylases in cancer therapy, covering their structural features, regulatory mechanisms, and functions. KDM6 plays complex roles in human cancers, acting as either a tumor suppressor or an oncoprotein. Potential therapy approaches based on the characteristics and mechanisms of KDM6 enzymes are proposed.
FRONTIERS IN ONCOLOGY
(2021)
Article
Plant Sciences
Takashi Maruoka, Eng-Seng Gan, Nana Otsuka, Makoto Shirakawa, Toshiro Ito
Summary: In Arabidopsis thaliana, histone demethylases JMJ30 and JMJ32 play a role in braking vernalization by activating FLC gene, leading to a faster silencing of FLC and accelerating flowering under moderate vernalized conditions.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Meiting Yang, Xiaorong Li, Zizi Tian, Lulu Ma, Jun Ma, Yunlong Liu, Guohui Shang, Ailing Liang, Wei Wu, Zhongzhou Chen
Summary: Recent research has discovered the MPND protein as a potential sensor for recognizing DNA 6mA modification in eukaryotes. Crystal structures of apo-MPND and MPND-DNA complex were determined, revealing dynamic assemblies. MPND was found to directly bind to histones and the interaction between MPND and histones was enhanced by DNA and the acidic regions of MPND. These findings provide structural information for further research on gene control and transcriptional regulation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Clinical Neurology
Lea M. Stitzlein, Achintyan Gangadharan, Leslie M. Walsh, Deokhwa Nam, Alexsandra B. Espejo, Melissa M. Singh, Kareena H. Patel, Yue Lu, Xiaoping Su, Ravesanker Ezhilarasan, Joy Gumin, Sanjay Singh, Erik Sulman, Frederick F. Lang, Joya Chandra
Summary: In this study, the efficacy of LSD1 inhibitors in patient-derived glioblastoma stem cell (GSC) models was evaluated. The results showed that LSD1 inhibitors had selective cytotoxic effects, but tumor regrowth occurred. Genes that may predict resistance to LSD1 inhibitors were identified using RNA-seq, providing guidance for future combination therapies.
FRONTIERS IN NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
K. Dhanalakshmi, Seiki Kuramitsu, Shigeyuki Yokoyama, Kumarevel Thirumananseri, Karthe Ponnuraj
Summary: This study reports the crystal structure of arginase from Thermus thermophilus (TtArginase), and compares it with other homologous structures. The results show that TtArginase is more stable compared to its mesophilic counterpart, Bacillus subtilis arginase (BsArginase). Additionally, the study reveals the critical role of metal ions in both the catalytic function and maintenance of proper active site geometry. These findings are important for optimizing the enzymatic action of arginase in various conditions.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
K. Dhanalakshmi, Seiki Kuramitsu, Shigeyuki Yokoyama, Thirumananseri Kumarevel, Karthe Ponnuraj
Summary: The crystal structure of pyrrolidone carboxyl peptidase from Thermus thermophilus (TtPCP) was solved and refined at 1.9 angstrom resolution using the molecular replacement method. Comparing TtPCP with its structural homologs, it was found that the putative thermal stability of TtPCP may be attributed to more intra and inter-molecular hydrogen bonds, hydrophobic and ion pair interactions. This structural information of TtPCP can contribute to understanding the intrinsic stability of thermophilic proteins and can be useful for protein engineering.
BIOPHYSICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Hideaki Ohtomo, Shinsuke Ito, Nicholas J. McKenzie, Michael Uckelmann, Masatoshi Wakamori, Haruhiko Ehara, Ayako Furukawa, Yasuo Tsunaka, Marika Shibata, Shun-ichi Sekine, Takashi Umehara, Chen Davidovich, Haruhiko Koseki, Yoshifum Nishimura
Summary: PRC1 and PRC2 play important roles in epigenetic gene regulation. H2A ubiquitination by PRC1 promotes H3K27 methylation by PRC2 through altering the dynamics of H3-tail and its contacts with DNA, with the linker-DNA being crucial for this process.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Shohei Takase, Takashi Hiroyama, Fumiyuki Shirai, Yuki Maemoto, Akiko Nakata, Mayumi Arata, Seiji Matsuoka, Takeshi Sonoda, Hideaki Niwa, Shin Sato, Takashi Umehara, Mikako Shirouzu, Yosuke Nishigaya, Tatsunobu Sumiya, Noriaki Hashimoto, Ryosuke Namie, Masaya Usui, Tomokazu Ohishi, Shun-ichi Ohba, Manabu Kawada, Yoshihiro Hayashi, Hironori Harada, Tokio Yamaguchi, Yoichi Shinkai, Yukio Nakamura, Minoru Yoshida, Akihiro Ito
Summary: Sickle cell disease (SCD) is caused by beta-globin gene mutations. G9a inhibitors, including RK-701, have been proposed as therapeutic agents for inducing fetal globin expression. This study describes the development of RK-701 as a selective and non-genotoxic G9a inhibitor, which upregulates BGLT3 long non-coding RNA and induces gamma-globin expression. BGLT3 is identified as an essential factor for gamma-globin induction and its universal role suggests its importance in SCD treatment.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Mutsuko Kukimoto-Niino, Kentaro Ihara, Chiemi Mishima-Tsumagari, Mio Inoue, Yoshinori Fukui, Shigeyuki Yokoyama, Mikako Shirouzu
Summary: This study reveals the crystal structures of the catalytic DHR2 domain of mouse DOCK10, complexed with either Cdc42 or Rac1, and uncovers the unique dual activation mechanism of DOCK10.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Tatsuo Yanagisawa, Eiko Seki, Hiroaki Tanabe, Yoshifumi Fujii, Kensaku Sakamoto, Shigeyuki Yokoyama
Summary: Pairs of pyrrolysyl-tRNA synthetase (PylRS) and tRNA(Pyl) from Methanosarcina mazei and Methanosarcina barkeri are used for site-specific incorporations of non-canonical amino acids into proteins. Mutations in Methanomethylophilus alvus PylRS allow efficient binding with N-e-((((E)-cyclooct-2-en-1-yl)oxy)carbonyl)-L-lysine (TCO*Lys) but not with N-e-(p-ethynylbenzyloxycarbonyl)-L-lysine (pEtZLys).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Yosuke Nishigaya, Shohei Takase, Tatsunobu Sumiya, Ko Kikuzato, Tomohiro Sato, Hideaki Niwa, Shin Sato, Akiko Nakata, Takeshi Sonoda, Noriaki Hashimoto, Ryosuke Namie, Teruki Honma, Takashi Umehara, Mikako Shirouzu, Hiroo Koyama, Minoru Yoshida, Akihiro Ito, Fumiyuki Shirai
Summary: The study focused on identifying novel inhibitors of lysine methyltransferase G9a for cancer epigenetics. Using HTS hit rac-10a from the chemical library of the University of Tokyo, the researchers established the structure-activity relationship of substrate-competitive inhibitors. Further optimization led to the discovery of compound 26j as a potent inhibitor of G9a/GLP with selective inhibition against other methyltransferases. Compound 26j demonstrated dose-dependent attenuation of H3K9me2 levels, tumor growth inhibition in vitro, and inhibition of tumor initiation and growth in a mouse model.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Nan Liu, Tsuyoshi Konuma, Rajal Sharma, Deyu Wang, Nan Zhao, Lingling Cao, Ying Ju, Di Liu, Shuai Wang, Almudena Bosch, Yifei Sun, Siwei Zhang, Donglei Ji, Satoru Nagatoishi, Noa Suzuki, Masaki Kikuchi, Masatoshi Wakamori, Chengcheng Zhao, Chunyan Ren, Thomas Jiachi Zhou, Yaoyao Xu, Jamel Meslamani, Shibo Fu, Takashi Umehara, Kouhei Tsumoto, Satoko Akashi, Lei Zeng, Robert G. Roeder, Martin J. Walsh, Qiang Zhang, Ming-Ming Zhou
Summary: Histone lysine acylation, such as acetylation and crotonylation, plays a crucial role in gene transcription, but our understanding has been limited to transcriptional activation. This study reveals that histone H3 lysine 27 crotonylation (H3K27cr) is involved in gene transcriptional repression. The YEATS domain of GAS41 selectively recognizes H3K27cr in chromatin and forms a complex with SIN3A-HDAC1 co-repressors. The proto-oncogenic transcription factor MYC recruits the GAS41/SIN3A-HDAC1 complex to repress genes, including the cell-cycle inhibitor p21.
Article
Cell Biology
Kota Noritsugu, Takehiro Suzuki, Kosuke Dodo, Kenji Ohgane, Yasue Ichikawa, Kota Koike, Satoshi Morita, Takashi Umehara, Kenji Ogawa, Mikiko Sodeoka, Naoshi Dohmae, Minoru Yoshida, Akihiro Ito
Summary: TEAD transcription factors regulate the transcriptional output of Hippo signaling by phosphorylating YAP and TAZ as coactivators. Recent studies have shown that cysteine palmitoylation also plays a role in regulating TEAD activity. This study discovers lysine long-chain fatty acylation as another post-translational modification of TEADs. Lysine fatty acylation enhances the interaction between TEADs and YAP/TAZ, contributing to their transcriptional activity. Interestingly, lysine fatty acylation of TEADs increases upon Hippo signaling activation, despite a decrease in cysteine acylation. These findings provide new insights into the regulation of TEAD activity through fatty-acyl modifications.
Review
Genetics & Heredity
Nando Dulal Das, Hideaki Niwa, Takashi Umehara
Summary: The dynamic regulation of histone methylation and demethylation is crucial for gene expression regulation. Abnormal expression of histone lysine demethylases has been linked to various diseases, including intractable cancers, thus making them promising therapeutic targets. Recent advancements in epigenomics and chemical biology have resulted in the development of potent, specific, and in vivo effective small-molecule demethylase inhibitors. This review highlights emerging small-molecule inhibitors targeting histone lysine demethylases and their progress towards drug discovery.
Article
Biotechnology & Applied Microbiology
Nando D. Das, Jen-Chien Chang, Chung-Chau Hon, S. Thomas Kelly, Shinsuke Ito, Marina Lizio, Bogumil Kaczkowski, Hisami Watanabe, Keisuke Katsushima, Atsushi Natsume, Haruhiko Koseki, Yutaka Kondo, Aki Minoda, Takashi Umehara
Summary: This study found that H4K5acK8ac and H3K27ac signals have some overlap in binding to the super-enhancer transcription factor BRD4 at higher levels, but they also have distinct specificities, especially in glioblastoma stem-like cell lines. Deletion of H4K5acK8ac-preferred super-enhancers associated with MYCN and NFIC resulted in a reduction in stem-like properties.
Article
Multidisciplinary Sciences
Masaki Kikuchi, Satoshi Morita, Masatoshi Wakamori, Shin Sato, Tomomi Uchikubo-Kamo, Takehiro Suzuki, Naoshi Dohmae, Mikako Shirouzu, Takashi Umehara
Summary: In this study, the authors discovered that p300/CBP recognizes and acetylates histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome, and also acetylates non-H4 histone NTs within the same nucleosome. The authors propose a model in which p300/CBP replicates histone N-terminal tail acetylation within the H3-H4 tetramer and transfers it to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
NATURE COMMUNICATIONS
(2023)
Article
Immunology
Seisuke Kusano, Sho Ueda, Daisuke Oryoji, Aya Toyoumi, Akiko Hashimoto-Tane, Hiroyuki Kishi, Hiroshi Hamana, Atsushi Muraguchi, Hui Jin, Hisashi Arase, Hiroko Miyadera, Reiko Kishikawa, Yasunobu Yoshikai, Hisakata Yamada, Ken Yamamoto, Yasuharu Nishimura, Takashi Saito, Takehiko Sasazuki, Shigeyuki Yokoyama
Summary: Cry j 1 is a major allergen in Japanese cedar pollens. The NF region of Cry j 1 peptide plays a role in enhancing T-cell activation. Mutation of Ser and Lys in the NF region to Glu reduces the affinity for HLA-DP5, antigen presentation, and T-cell activation.
INTERNATIONAL IMMUNOLOGY
(2023)
Article
Chemistry, Medicinal
Yosuke Nishigaya, Shohei Takase, Tatsunobu Sumiya, Ko Kikuzato, Tomohiro Sato, Hideaki Niwa, Shin Sato, Akiko Nakata, Takeshi Sonoda, Noriaki Hashimoto, Ryosuke Namie, Teruki Honma, Takashi Umehara, Mikako Shirouzu, Hiroo Koyama, Minoru Yoshida, Akihiro Ito, Fumiyuki Shirai
Summary: Identification of structurally novel inhibitors of lysine methyltransferase G9a was performed using high-throughput screening and molecular analysis. Compound 26j (RK-701) was identified as a potent and selective inhibitor of G9a/GLP, showing dose-dependent attenuation of H3K9me2 levels and tumor growth inhibition in vitro and in a mouse model of hepatocellular carcinoma.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Yosuke Nishigaya, Shohei Takase, Tatsunobu Sumiya, Ko Kikuzato, Tomohiro Sato, Hideaki Niwa, Shin Sato, Akiko Nakata, Takeshi Sonoda, Noriaki Hashimoto, Ryosuke Namie, Teruki Honma, Takashi Umehara, Mikako Shirouzu, Hiroo Koyama, Minoru Yoshida, Akihiro Ito, Fumiyuki Shirai
Summary: The study successfully identified a novel G9a inhibitor with important significance in cancer epigenetics. Starting from a compound called rac-10a obtained from the chemical library, the structure-activity relationship of the substrate-competitive inhibitors was established using X-ray crystallography and fragment molecular orbital calculations. Further optimization led to the identification of compound 26j (RK-701), which showed potent inhibition of G9a/GLP with high selectivity and demonstrated significant inhibition of tumor growth in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
