Review
Cell Biology
Natalia Lourenco de Freitas, Maria Gabriela Deberaldini, Diana Gomes, Aline Renata Pavan, Angela Sousa, Jean Leandro Dos Santos, Christiane P. Soares
Summary: Epigenetic modifications, particularly histone acetylation, play a crucial role in cancer development by regulating gene expression. HDAC inhibitors show promise as a potential therapy for HPV-related cervical cancer treatment.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Qian Hui, Lihui Zhang, Jinhong Feng, Lei Zhang
Summary: Inhibition of histone deacetylases (HDACs) has been extensively studied for the development of anticancer drugs. In this study, novel HDAC inhibitors were discovered by introducing the 2-substituted phenylquinoline-4-carboxylic acid group. A total of 30 compounds were synthesized and tested for their inhibitory activity against HDAC enzymes. Among them, D28 and D29 showed significant selectivity towards HDAC3. However, despite their improved enzyme inhibitory activity, the hydrazide-bearing compounds did not exhibit significant anticancer potency in vitro.
FRONTIERS IN CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Hae Jin Kee, Inkyeom Kim, Myung Ho Jeong
Summary: This article provides an overview of the pathogenesis of hypertension, current anti-hypertensive drugs, and the need for novel drugs. It focuses on the role and regulatory mechanisms of HDACs in hypertension and discusses the progress in developing HDAC inhibitors as potential therapeutic targets.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Cell Biology
Kai Xue, Ji-Chuan Wu, Xi-Ya Li, Ran Li, Qun-ling Zhang, Jin-Jia Chang, Yi-Zhen Liu, Chun-Hui Xu, Jia-Ying Zhang, Xiao-Jian Sun, Juan J. Gu, Wei-Jian Guo, Lan Wang
Summary: The study demonstrated that chidamide showed therapeutic effects in rituximab/chemotherapy resistant B-cell lymphoma by inhibiting cell growth, inducing cell death, and activating autophagy pathway. Chidamide targeted BTG1 and FOXO1 genes, regulating autophagy and cell cycle, and enhanced the efficacy when combined with cisplatin in a synergistic manner. These findings provide a theoretical and mechanistic basis for further evaluation of chidamide-based treatment in relapsed and refractory B-cell lymphoma patients.
CELL DEATH & DISEASE
(2021)
Article
Dermatology
Lina Song, Anne Catherine Bretz, Jan Gravemeyer, Ivelina Spassova, Shakhlo Muminova, Thilo Gambichler, Ashwin Sriram, Soldano Ferrone, Juergen C. Becker
Summary: Merkel cell carcinoma is a rare and highly aggressive skin cancer, with immune modulation by immune checkpoint inhibitors showing promise. However, resistance to immunotherapy remains a significant challenge. Histone deacetylase inhibitors like domatinostat have shown potential to reverse low MHC I expression and increase MCC cells' susceptibility to cytotoxic T cell recognition and elimination.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2021)
Article
Multidisciplinary Sciences
Iva Kelava, Ilaria Chiaradia, Laura Pellegrini, Alex T. Kalinka, Madeline A. Lancaster
Summary: By using brain organoids, this study reveals that androgens preferentially increase the proliferation of cortical progenitors and the neurogenic pool, which contributes to the understanding of the origin of sex-related brain differences in humans.
Article
Chemistry, Medicinal
Hualong Mo, Ruiqiang Zhang, Yajun Chen, ShuTing Li, Yao Wang, Wenbo Zou, Qiman Lin, Deng-Gao Zhao, Yarong Du, Kun Zhang, Yan-Yan Ma
Summary: Compound 21 is an effective anticancer agent that inhibits tumor growth by inhibiting autophagy and inducing cell apoptosis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
William Villiers, Audrey Kelly, Xiaohan He, James Kaufman-Cook, Abdurrahman Elbasir, Halima Bensmail, Paul Lavender, Richard Dillon, Borbala Mifsud, Cameron S. Osborne
Summary: The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Dimitrios Triantafyllos Gerokonstantis, Christiana Mantzourani, Dimitrios Gkikas, Kai-Chen Wu, Huy N. Hoang, Ierasia Triandafillidi, Ilianna Barbayianni, Paraskevi Kanellopoulou, Alexandros C. Kokotos, Panagiota Moutevelis-Minakakis, Vassilis Aidinis, Panagiotis K. Politis, David P. Fairlie, George Kokotos
Summary: Benzamides, as HDAC inhibitors, have shown promising anticancer activity and potential for treating fibrotic disorders.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Gastroenterology & Hepatology
Li Du, Dongyuan Wang, Xiuqi Wei, Chang Liu, Zhuanglong Xiao, Wei Qian, Yuhu Song, Xiaohua Hou
Summary: The study demonstrates that Class I selective HDAC inhibitor MS275 effectively inhibits the development of malignant ascites and tumor growth through multiple pathways, including inducing cell cycle arrest and promoting apoptosis. MS275 can also impact the expression of proteins related to cell progression and regulate tumor-related proteins, enhancing its anti-tumor effects.
BMC GASTROENTEROLOGY
(2022)
Review
Biochemistry & Molecular Biology
Svetlana Demyanenko, Valentina Dzreyan, Svetlana Sharifulina
Summary: Cerebral ischemia is the second leading cause of death worldwide, requiring multimodal stroke therapy. Histone deacetylase inhibitors have shown to be effective in protecting the brain from ischemic damage by inducing neurogenesis and angiogenesis in damaged brain areas, promoting functional recovery after stroke.
Review
Medicine, Research & Experimental
Shigeki Saito, Brian Deskin, Mohammad Rehan, Santosh Yadav, Yasuka Matsunaga, Joseph A. Lasky, Victor J. Thannickal
Summary: Lung fibrosis can occur in various settings, and the most common form is idiopathic pulmonary fibrosis, which is strongly associated with aging. Recent studies suggest that targeting certain components of aging biology may be effective in mitigating age-related fibrosis. This review explores molecular targets that may be relatively more selective in mediating tissue fibrosis, as well as epigenetic mechanisms and metabolic pathways that regulate aging and fibrosis.
Article
Chemistry, Medicinal
Nan Sun, Kexin Yang, Wenzhong Yan, Mingyue Yao, Chengying Xie, Jianjun Cheng, Chengcheng Yu, Wenwen Duan, Xiaoke Gu, Dong Guo, Hualiang Jiang
Summary: Compound 19h, a novel HDAC inhibitor, showed potent and selective inhibition of HDAC1 and exhibited good antiproliferative activity in vitro. It significantly inhibited the growth of human tumor xenografts and murine tumor in animal models. When combined with the mPD-1 antibody, 19h increased the ratio of splenic CD4+ T effector cells and promoted complete tumor regression in 5/6 animals in the MC38 model. These findings suggest that selective class I HDAC inhibitors have direct tumor growth inhibition and indirect immune cell-mediated antitumor effects, and synergize with immune checkpoint inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Hans K. Ghayee, Yiling Xu, Heather Hatch, Richard Brockway, Asha S. Multani, Tongjun Gu, Wendy B. Bollag, Adina Turcu, William E. Rainey, Juilee Rege, Kazutaka Nanba, Vikash J. Bhagwandin, Fiemu Nwariaku, Victor Stastny, Adi F. Gazdar, Jerry W. Shay, Richard J. Auchus, Sergei G. Tevosian
Summary: The human adrenal cortex consists of distinct zones and is the main source of steroid hormone production. Understanding the mechanism of adrenocortical cell differentiation has been challenging, but a patient-derived HAA1 cell line has been discovered that shows unique gene expression patterns upon treatment with histone deacetylase inhibitors. This novel cell line could provide valuable insights into adrenocortical differentiation and steroidogenesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Agricultural Engineering
Xuefeng Lu, Tae Kyung Hyun
Summary: Post-translational histone modifications, such as histone acetylation, play key roles in regulating gene expression in plant growth, development, and stress responses. The research found that HDAC inhibitors led to hyperacetylation of histone H3, enhancing MeJA-induced ginsenoside production in ginseng adventitious roots. Additionally, the study identified specific PgHDACs that may serve as crucial factors in controlling MeJA-induced ginsenoside production.
INDUSTRIAL CROPS AND PRODUCTS
(2021)
Article
Multidisciplinary Sciences
Conor J. Kearney, Stephin J. Vervoort, Kelly M. Ramsbottom, Izabela Todorovski, Emily J. Lelliott, Magnus Zethoven, Lizzy Pijpers, Ben P. Martin, Timothy Semple, Luciano Martelotto, Joseph A. Trapani, Ian A. Parish, Nichollas E. Scott, Jane Oliaro, Ricky W. Johnstone
Summary: SUGAR-seq is a novel method that enables simultaneous detection of N-linked glycosylation, extracellular epitopes, and the transcriptome at the single-cell level, providing insights into cellular differentiation states. Integrated analysis using SUGAR-seq and glycoproteome identified tumor-infiltrating T cells with unique surface glycan properties that reflect their epigenetic and functional state.
Article
Biochemistry & Molecular Biology
Stephin J. Vervoort, Sarah A. Welsh, Jennifer R. Devlin, Elisa Barbieri, Deborah A. Knight, Sarah Offley, Stefan Bjelosevic, Matteo Costacurta, Izabela Todorovski, Conor J. Kearney, Jarrod J. Sandow, Zheng Fan, Benjamin Blyth, Victoria McLeod, Joseph H. A. Vissers, Karolina Pavic, Ben P. Martin, Gareth Gregory, Elena Demosthenous, Magnus Zethoven, Isabella Y. Kong, Edwin D. Hawkins, Simon J. Hogg, Madison J. Kelly, Andrea Newbold, Kaylene J. Simpson, Otto Kauko, Kieran F. Harvey, Michael Ohlmeyer, Jukka Westermarck, Nathanael Gray, Alessandro Gardini, Ricky W. Johnstone
Summary: CDK9 regulates gene expression by controlling the pausing checkpoint during the transcription cycle, while PP2A counteracts CDK9-mediated phosphorylation. Loss of INTS6 leads to resistance to CDK9 inhibition-induced tumor cell death, and pharmacological activation of PP2A in combination with CDK9 inhibition provides therapeutic benefits in vivo.
Article
Oncology
Lin Xiao, Klaartje Somers, Jayne Murray, Ruby Pandher, Mawar Karsa, Emma Ronca, Angelika Bongers, Rachael Terry, Anahid Ehteda, Laura D. Gamble, Natalia Issaeva, Katerina I. Leonova, Aisling O'Connor, Chelsea Mayoh, Pooja Venkat, Hazel Quek, Jennifer Brand, Frances K. Kusuma, Jessica A. Pettitt, Erin Mosmann, Adam Kearns, Georgina Eden, Stephanie Alfred, Sophie Allan, Lei Zhai, Alvin Kamili, Andrew J. Gifford, Daniel R. Carter, Michelle J. Henderson, Jamie I. Fletcher, Glenn Marshall, Ricky W. Johnstone, Anthony J. Cesare, David S. Ziegler, Andrei V. Gudkov, Katerina V. Gurova, Murray D. Norris, Michelle Haber
Summary: The combination of CBL0137 and panobinostat enhances nucleosome destabilization, induces an IFN response, inhibits DNA damage repair, and synergistically suppresses cancer cell growth, showing promising potential for addition to immunotherapies.
CLINICAL CANCER RESEARCH
(2021)
Article
Multidisciplinary Sciences
Mayura Wagle, Stephin J. Vervoort, Madison J. Kelly, Willem Van der Byl, Timothy J. Peters, Ben P. Martin, Luciano G. Martelotto, Simone Nuessing, Kelly M. Ramsbottom, James R. Torpy, Deborah Knight, Sinead Reading, Kevin Thia, Lisa A. Miosge, Debbie R. Howard, Renee Gloury, Sarah S. Gabriel, Daniel T. Utzschneider, Jane Oliaro, Jonathan D. Powell, Fabio Luciani, Joseph A. Trapani, Ricky W. Johnstone, Axel Kallies, Christopher C. Goodnow, Ian A. Parish
Summary: Chronic antigenic stimulation induces the expression of EGR2, which in turn affects the epigenetic and transcriptional identity of exhausted T cells.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Emily J. Lelliott, Isabella Y. Kong, Magnus Zethoven, Kelly M. Ramsbottom, Luciano G. Martelotto, Deborah Meyran, Joe Jiang Zhu, Matteo Costacurta, Laura Kirby, Jarrod J. Sandow, Lydia Lim, Pilar M. Dominguez, Izabela Todorovski, Nicole M. Haynes, Paul A. Beavis, Paul J. Neeson, Edwin D. Hawkins, Grant A. McArthur, Ian A. Parish, Ricky W. Johnstone, Jane Oliaro, Karen E. Sheppard, Conor J. Kearney, Stephin J. Vervoort
Summary: Pharmacologic inhibitors of CDK4/6 have been shown to not only have well-defined tumor-intrinsic cytostatic mechanisms, but also promote the acquisition of immunologic T-cell memory. These insights significantly broaden the potential utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity.
Article
Oncology
Aesha Ali, Minyu Wang, Bianca von Scheidt, Pilar M. Dominguez, Aaron J. Harrison, Daniela G. M. Tantalo, Jian Kang, Amanda J. Oliver, Jack D. Chan, Xin Du, Yuchen Bai, Belinda Lee, Ricky W. Johnstone, Phillip K. Darcy, Michael H. Kershaw, Clare Y. Slaney
Summary: The study demonstrated the effectiveness of a combination chimeric antigen receptor (CAR) T-cell therapy in eradicating the majority of tumors in murine and human pancreatic cancer models, involving dual-specific CAR T cells, a vaccine to activate CAR T cells, and treatment with the histone deacetylase inhibitor panobinostat (Pano).
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Lisa C. Wellinger, Simon J. Hogg, Dane M. Newman, Thomas Friess, Daniela Geiss, Jessica Michie, Kelly M. Ramsbottom, Marina Bacac, Tanja Fauti, Daniel Marbach, Laura Jarassier, Phillip Thienger, Axel Paehler, Leonie A. Cluse, Conor J. Kearney, Stephin J. Vervoort, Joseph A. Trapani, Jane Oliaro, Jake Shortt, Astrid Ruefli-Brasse, Daniel Rohle, Ricky W. Johnstone
Summary: Targeting chromatin binding proteins and modifying enzymes can enhance antitumor immunity and effectiveness of cancer immunotherapies by affecting tumor cell proliferation and survival. BET inhibitors sensitize tumor cells to TNF-induced cell death and suppress inflammatory gene expression, leading to enhanced tumor growth inhibition in combination with T-cell bispecific antibodies or immune-checkpoint blockade.
CANCER IMMUNOLOGY RESEARCH
(2022)
Article
Hematology
Lauren M. Brown, Soroor Hediyeh-Zadeh, Teresa Sadras, Hannah Huckstep, Jarrod J. Sandow, Ray C. Bartolo, Hansen J. Kosasih, Nadia M. Davidson, Breon Schmidt, Stefan Bjelosevic, Ricky Johnstone, Andrew Webb, Seong L. Khaw, Alicia Oshlack, Melissa J. Davis, Paul G. Ekert
Summary: This study identified a rare SFPQ-ABL1 fusion gene that plays a crucial role in cellular transformation in Ph-like ALL. Unlike other ABL1 fusion genes, SFPQ-ABL1 exhibits differences in subcellular localization, proliferative capacity, and activation of cellular pathways. These findings highlight the significance of fusion partners in mediating the function of ABL1 fusion genes.
Article
Medicine, Research & Experimental
Joan So, Alexander C. Lewis, Lorey K. Smith, Kym Stanley, Rheana Franich, David Yoannidis, Lizzy Pijpers, Pilar Dominguez, Simon J. Hogg, Stephin J. Vervoort, Fiona C. Brown, Ricky W. Johnstone, Gabrielle McDonald, Danielle B. Ulanet, Josh Murtie, Emily Gruber, Lev M. Kats
Summary: The study reveals that DHODH inhibitors have potent and selective activity against AML, and can reverse the differentiation block in AML cells. In addition, the elimination of the CDK5 gene increases the sensitivity of AML cells to DHODHi.
EMBO MOLECULAR MEDICINE
(2022)
Article
Oncology
Jessica M. Salmon, Izabela Todorovski, Kym L. Stanley, Claudia Bruedigam, Conor J. Kearney, Luciano G. Martelotto, Fernando Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A. Cluse, Peter J. Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y. Matthews, Elise Gressier, Nicole A. de Weerd, Jens Lichte, Madison J. Kelly, Simon J. Hogg, Paul J. Hertzog, Lev M. Kats, Stephin J. Vervoort, Daniel D. De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T. Kile, Steven W. Lane, Andrew C. Perkins, Andrew H. Wei, Pilar M. Dominguez, Ricky W. Johnstone
Summary: Inhibition of HDACs can induce differentiation and therapeutic effects in AML cells, and epigenetic rewiring of pDCs enhances antitumor immunity, offering a new therapeutic approach.
Article
Oncology
Lin Xiao, Mawar Karsa, Emma Ronca, Angelika Bongers, Angelika Kosciolek, Ali El-Ayoubi, Jezrael L. Revalde, Janith A. Seneviratne, Belamy B. Cheung, Laurence C. Cheung, Rishi S. Kotecha, Andrea Newbold, Stefan Bjelosevic, Greg M. Arndt, Richard B. Lock, Ricky W. Johnstone, Andrei V. Gudkov, Katerina V. Gurova, Michelle Haber, Murray D. Norris, Michelle J. Henderson, Klaartje Somers
Summary: The combination of CBL0137 and the HDAC inhibitor panobinostat shows promising therapeutic potential in KMT2A-rearranged leukemia, enhancing treatment efficacy and extending patient survival.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Isabella Y. Kong, Stephanie Trezise, Amanda Light, Izabela Todorovski, Gisela Mir Arnau, Sreeja Gadipally, David Yoannidis, Kaylene J. Simpson, Xueyi Dong, Lachlan Whitehead, Jessica C. Tempany, Anthony J. Farchione, Amania A. Sheikh, Joanna R. Groom, Kelly L. Rogers, Marco J. Herold, Vanessa L. Bryant, Matthew E. Ritchie, Simon N. Willis, Ricky W. Johnstone, Philip D. Hodgkin, Stephen L. Nutt, Stephin J. Vervoort, Edwin D. Hawkins
Summary: Integrated phenotype-transcriptome analyses can effectively uncover the molecular circuitry that regulates lymphocyte fate decisions.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Cell Biology
Emily Gruber, Joan So, Alexander C. Lewis, Rheana Franich, Rachel Cole, Luciano G. Martelotto, Amy J. Rogers, Eva Vidacs, Peter Fraser, Kym Stanley, Lisa Jones, Anna Trigos, Niko Thio, Jason Li, Brandon Nicolay, Scott Daigle, Adriana E. Tron, Marc L. Hyer, Jake Shortt, Ricky W. Johnstone, Lev M. Kats
Summary: A study found that the efficacy of the IDH1 inhibitor AG-120 in AML patients depends on the cell type. Although AG-120 as a single agent cannot completely eradicate the disease, it can increase the proliferation of leukemia stem cells and enhance sensitivity to azacitidine. Therefore, the combination therapy of AG-120 and azacitidine shows improved efficacy in patients.
Article
Oncology
Simon J. Hogg, Olga Motorna, Conor J. Kearney, Emily B. Derrick, Imran G. House, Izabela Todorovski, Madison J. Kelly, Magnus Zethoven, Kenneth D. Bromberg, Albert Lai, Paul A. Beavis, Jake Shortt, Ricky W. Johnstone, Stephin J. Vervoort
Summary: This study characterized the acute epigenetic changes induced by IFN gamma stimulation in a murine breast cancer model using transcriptomic and epigenomic profiling. Results showed that IFN gamma activated specific cis-regulatory elements, leading to increased chromatin accessibility, differential usage of pro-inflammatory enhancers, and recruitment of downstream proteins. Functional validation experiments revealed that histone acetylation played a crucial role in IFN gamma-driven transcription, and targeting the activity of P300/CBP acetyltransferase could suppress the epigenetic remodeling induced by IFN gamma.
CLINICAL EPIGENETICS
(2022)
Review
Oncology
Stephin J. Vervoort, Jennifer R. Devlin, Nicholas Kwiatkowski, Mingxing Teng, Nathanael S. Gray, Ricky W. Johnstone
Summary: Accurate control of gene expression is crucial for normal development and any dysregulation can lead to cancer initiation and progression. The transcription process can be viewed as a multistep cycle, with dysregulation potentially causing defective gene expression control in cancer. Targeting transcriptional cyclin-dependent kinases and associated proteins may hold promise for cancer treatment by disrupting global or selective transcription.
NATURE REVIEWS CANCER
(2022)