Histone acetylation alteration by KAT6A inhibitor WM-1119 suppresses IgE-mediated mast cell activation and allergic inflammation via reduction in AP-1 signaling

Article

Author: Ji, Kunmei ; Liu, Shan ; Jiao, Yu-Xin ; Zhou, Yan-Mei ; Xu, Xue-Ting ; Chen, Jia-Jie ; He, Yong ; Zhou, Zi-Wen

Activation of immunoglobulin E (IgE)-associated mast cells (MCs) triggers the onset of pro-inflammatory signals associated with type I allergic diseases. Although histone acetylation changes have been associated with inflammatory diseases, the impact of lysine-acetyltransferase (KAT) inhibitors on IgE-mediated MCs function is unclear. Potential anti-allergic effects of the KAT6A inhibitor WM-1119 on IgE-mediated MCs activation and allergic inflammation were examined in this study. WM-1119 was observed to reduce IgE-mediated degranulation in rat basophilic leukemia-2H3 cells (RBLs) and murine bone marrow-derived mast cells (BMMCs), as demonstrated by reduced the release of β-hexosaminidase (β-hex)or histamine(HA) and decreased inflammatory cytokines. Additionally, WM-1119 attenuated allergic responses in IgE-induced passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) mice. No WM-1119 effects on histamine-induced hypothermia in mice were observed. Mechanically, WM-1119 reduced levels of histone H3 lysine 14 acetylation (H3K14ac) and H3K27ac, while also reducing IgE-induced MAPK or NF-κB activity. Moreover, WM-1119 reduced activator protein-1 (AP-1) activity in a manner involving inhibition of c-Fos transcription and translation together with decreased AP-1 binding of its downstream promoters. KAT6A knockdown in MCs also reduced AP-1 activity by inhibiting c-Fos expression. H3K14ac enrichment in the Fos promoter was observed, indicating that H3K14ac may regulate c-Fos expression. In conclusion, KAT6A inhibition or knockdown was shown to reduce IgE-mediated MCs activation and allergic inflammation through a mechanism involving changes in c-Fos expression and downstream AP-1 activity consequent to down-regulation of histone acetylation. KAT6A inhibition may represent a new treatment strategy for suppressing MCs in treating allergic diseases.

25 Jun 2024·Proceedings of the National Academy of Sciences

A MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes

Article

Author: Smolko, Anne E. ; Kang, Hyuckjoon ; Sullivan, Daniel W. ; Kuroda, Mitzi I. ; Baell, Jonathan B. ; Whedon, Samuel D. ; Cole, Philip A. ; Armstrong, Scott A. ; Olsen, Sarah Naomi

Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alterations of these proteins, often enzymes, can be targeted therapeutically. MOZ, a histone acyltransferase, is recurrently fused to coactivators CBP, p300, and TIF2 in cases of acute myeloid leukemia (AML). Using either pharmacological inhibition or targeted protein degradation in a mouse model for MOZ-TIF2-driven leukemia, we show that KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein are necessary for indefinite proliferation in cell culture. MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors, augmenting their high expression. Furthermore, transcription levels in MOZ-TIF2 cells positively correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr), a recently appreciated histone acylation associated with gene activation. Unexpectedly, we also show that MOZ-TIF2 and MLL-AF9 regulate transcription of unique gene sets, and their cellular models exhibit distinct sensitivities to multiple small-molecule inhibitors directed against AML pathways. This is despite the shared genetic pathways of wild-type MOZ and MLL. Overall, our data provide insight into how aberrant regulation of MOZ contributes to leukemogenesis. We anticipate that these experiments will inform future work identifying targeted therapies in the treatment of AML and other diseases involving MOZ-induced transcriptional dysregulation.

01 Jan 2023·Leukemia

Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia

Article

Author: Bywater, Megan J ; Baell, Jonathan ; Bullinger, Lars ; Cooper, Emily ; Straube, Jasmin ; Jacquelin, Sebastien ; Tey, Siok-Keen ; Janardhanan, Yashaswini ; Bruedigam, Claudia ; Tavakoli Shirazi, Paniz ; Huang, Fei ; Jin, Jianwen ; Godfrey, William ; Haldar, Rohit ; Cooper, Leanne ; Lane, Steven W ; Ling, Victoria Y ; Zhao, Yichao

Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G₁S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.

100 Deals associated with WM-1119

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Phase 3	Australia	Monash University	01 Aug 2018
Hepatocellular Carcinoma	Phase 3	China	Nanjing Tech University	01 Aug 2018
Lymphoma	Phase 3	Australia	Monash University	01 Aug 2018
Lymphoma	Phase 3	China	Nanjing Tech University	01 Aug 2018
Neoplasms	Preclinical	Australia	Monash University	02 Mar 2020

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