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)
Review
Cell Biology
Dawid Dorna, Jaroslaw Paluszczak
Summary: Epigenetic aberrations, including altered DNA methylation and histone modifications, are commonly found in head and neck squamous cell carcinomas (HNSCC). Histone lysine demethylases (KDMs) have been implicated in the pathogenesis of HNSCC and are potential therapeutic targets. These enzymes play a role in transcriptional regulation and various biological processes. Overexpression of KDMs in HNSCC affects cell proliferation, apoptosis, cell motility, and stemness.
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
Sara Ribeiro, Anna M. Eiring, Jamshid S. Khorashad
Summary: AML is a heterogeneous malignancy with various genetic abnormalities, some of which have led to the development of specific inhibitors approved by the FDA for eligible patients. Cytogenetic profiling and gene mutation analysis are essential for the diagnosis, classification, prognosis, and treatment of AML. The review discussed genomic abnormalities in AML, the significance of certain gene mutations as therapeutic targets, and the limitations of current genomic approaches in producing a comprehensive understanding of the disease.
Article
Hematology
Svea Stratmann, Sara A. Yones, Markus Mayrhofer, Nina Norgren, Aron Skaftason, Jitong Sun, Karolina Smolinska, Jan Komorowski, Morten Krogh Herlin, Christer Sundstrom, Anna Eriksson, Martin Hoglund, Josefine Palle, Jonas Abrahamsson, Kirsi Jahnukainen, Monica Cheng Munthe-Kaas, Bernward Zeller, Katja Pokrovskaja Tamm, Lucia Cavelier, Linda Holmfeldt
Summary: AML is the leading cause of death in adult and pediatric patients, with specific differences in mutational spectrum at relapse. Key genes ARID1A and CSF1R show recurrent mutations at relapse, while new gene mutations identified may play important roles in disease progression and therapy resistance, providing possibilities for personalized medicine.
Article
Oncology
Hui Zhou, Yuelong Jiang, Yuetin Huang, Mengya Zhong, Dongmei Qin, Chendi Xie, Guangchao Pan, Jinshui Tan, Manman Deng, Haijun Zhao, Yong Zhou, Yuanfang Tang, Qian Lai, Zhihong Fang, Yiming Luo, Yirong Jiang, Bing Xu, Jie Zha
Summary: Treatment of AML with chemotherapeutic agents is ineffective in eliminating LSC, leading to high risk of relapse. This study found that targeting PPAR alpha with chiglitazar can effectively inhibit glycolysis and induce apoptosis in AML cells. In vivo experiments using AML PDX models also demonstrated the ability of chiglitazar to kill LSC. Thus, targeting PPAR alpha presents a promising therapeutic approach for AML.
Review
Oncology
Sreoshee Rafiq, Sharon L. McKenna, Sylviane Muller, Mario P. Tschan, Magali Humbert
Summary: Lysosomes, traditionally known for degrading cellular macromolecules, have emerged as crucial regulators of cell homeostasis. Their involvement in cellular trafficking, nutrient signaling, energy metabolism, and immune regulation has sparked interest in targeting lysosomes for novel disease treatments, particularly cancer. This review highlights the diverse functions of lysosomes and their importance in malignant disease, with a focus on potential targeting strategies in acute myeloid leukemia (AML).
Review
Oncology
Benluvankar Varghese, Nunzio Del Gaudio, Gilda Cobellis, Lucia Altucci, Angela Nebbioso
Summary: Breast cancer is the second leading cause of cancer death in women, with genetic mutations and epigenetic modifications playing a critical role in its progression. The KDM4 enzymes are considered potential therapeutic targets for breast cancer, but the lack of selective inhibitors has hindered their entry into clinical trials.
FRONTIERS IN ONCOLOGY
(2021)
Article
Health Care Sciences & Services
David J. Wooten, Melat Gebru, Hong-Gang Wang, Reka Albert
Summary: The study investigated the gene expression changes in FLT3-mutant AML cell lines in response to drug treatment, identifying seven gene programs involved in AML drug-induced changes. By constructing a network of FLT3-ITD AML and applying the BooleaBayes algorithm, a probabilistic, data-driven dynamical model of acquired resistance to drugs was created, revealing potential interventions to disrupt the drug response system and prevent resistance.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Oncology
Ipek Bulut, Adam Lee, Buse Cevatemre, Dusan Ruzic, Roman Belle, Akane Kawamura, Sheraz Gul, Katarina Nikolic, A. Ganesan, Ceyda Acilan
Summary: The newly developed LSD1/HDAC6 dual inhibitor iDual can inhibit the growth of leukemia cells by simultaneously targeting HDAC6 and LSD1, and it can enhance drug-induced apoptosis when used in combination with doxorubicin.
Article
Medicine, Research & Experimental
Yinghui Li, Chaoqun Wang, Huier Gao, Jiali Gu, Yiran Zhang, Yingyi Zhang, Min Xie, Xuelian Cheng, Ming Yang, Wenshan Zhang, Yafang Li, Mei He, Hui Xu, Hexiao Zhang, Qing Ji, Tianhua Ma, Sheng Ding, Yu Zhao, Yingdai Gao
Summary: This study identified a specific KDM4 inhibitor, SD49-7, for resistant leukemia therapy, demonstrating its ability to inhibit the progression of leukemia stem cells (LSCs) and overcome resistance to traditional treatments.
Article
Chemistry, Medicinal
Xingrui He, Hang Zhang, Yingqian Zhang, Yang Ye, Shuo Wang, Renren Bai, Tian Xie, Xiang-Yang Ye
Summary: Post-translational modifications (PTMs) of histone by histone demethylases (KDMs) are important for gene expression regulation and are implicated in the development of various human cancers and diseases. This review surveys the latest small-molecule inhibitors of KDMs, focusing on literature since 2018, including inhibitors of lysine-specific demethylases (LSD or KDM1) and JmjC family N-methyl lysine demethylases (JmjC KDMs, i.e. KDM2-7). The review also discusses drug design strategy, structure-activity relationships (SARs), analysis of co-crystal structures, and mechanisms of action (MOA).
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Oncology
Jeries Abu-Hanna, Jigisha A. Patel, Evangelos Anastasakis, Richard Cohen, Lucie H. Clapp, Marilena Loizidou, Mohammad M. R. Eddama
Summary: This review examines and summarizes the therapeutic potential of inhibiting H3K27 demethylases, with a focus on the small-molecule inhibitor GSK-J4, based on pre-clinical in vitro and in vivo evidence.
CLINICAL EPIGENETICS
(2022)
Review
Genetics & Heredity
Gaya Punnia-Moorthy, Peter Hersey, Abdullah Al Emran, Jessamy Tiffen
Summary: This review focuses on the structure, classification, and functions of lysine demethylases (KDMs) in normal and cancer biology, with an emphasis on melanoma. Aberrant lysine demethylase activity has been implicated in various cancers. There are knowledge gaps regarding the role of KDMs in melanoma pathobiology.
FRONTIERS IN GENETICS
(2021)
Article
Pharmacology & Pharmacy
Robert Kleszcz, Marcin Skalski, Violetta Krajka-Kuzniak, Jaroslaw Paluszczak
Summary: This study investigated the anti-cancer effects of KDM4 and KDM6 inhibitors, both alone and in combination with EGFR and PI3K inhibitors, on HNSCC cells. The results showed that these compounds and their combinations induced apoptosis and were associated with changes in gene expression levels, suggesting that inhibition of KDM4 and KDM6 could be a novel therapeutic strategy in HNSCC.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Basusree Ghosh, Liberalis Debraj Boila, Susobhan Choudhury, Priya Mondal, Sayan Bhattacharjee, Samir Kumar Pal, Amitava Sengupta, Siddhartha Roy
ACS CHEMICAL BIOLOGY
(2018)
Article
Oncology
Shankha Subhra Chatterjee, Mayukh Biswas, Liberalis Debraj Boila, Debasis Banerjee, Amitava Sengupta
MOLECULAR CANCER RESEARCH
(2018)
Article
Biochemistry & Molecular Biology
Mayukh Biswas, Shankha Subhra Chatterjee, Liberalis Debraj Boila, Sayan Chakraborty, Debasis Banerjee, Amitava Sengupta
Review
Hematology
Liberalis Debraj Boila, Amitava Sengupta
EXPERIMENTAL HEMATOLOGY
(2020)
Article
Oncology
Liberalis Debraj Boila, Subhadeep Ghosh, Subham K. Bandyopadhyay, Liqing Jin, Alex Murison, Andy G. X. Zeng, Wasim Shaikh, Satyaki Bhowmik, Siva Sai Naga Anurag Muddineni, Mayukh Biswas, Sayantani Sinha, Shankha Subhra Chatterjee, Nathan Mbong, Olga I. Gan, Anwesha Bose, Sayan Chakraborty, Andrea Arruda, James A. Kennedy, Amanda Mitchell, Eric R. Lechman, Debasis Banerjee, Michael Milyavsky, Mark D. Minden, John E. Dick, Amitava Sengupta
Summary: Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with limited targeted therapies. This study found that KDM6-demethylase function critically regulates DNA-damage-repair-(DDR) gene expression in AML. KDM6A loss-of-function mutations are linked to chemoresistance, while upregulated KDM6A is associated with venetoclax tolerance. Combination therapy targeting PARP and BCL2 was shown to be superior in inducing AML apoptosis, particularly in AML cells carrying KDM6A-domain mutations. Therefore, KDM6A could be a potential molecular regulator for determining therapeutic efficacy in AML.
