TIP60 Inhibitor TH1834 Reduces Breast Cancer Progression in Xenografts in Mice

Idrissou, Mouhamed; Judes, Gaëlle; Daures, Marine; Sánchez, Alcides Antúnez; Ouardi, Driss El; Besse, Sophie; Degoul, Françoise; Penault‐Llorca, Frédérique; Bignon, Yves‐Jean; Bernard‐Gallon, Dominique

doi:10.1089/omi.2019.0126

Cited by 14 publications

(6 citation statements)

References 7 publications

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“…showed that a Tip60 inhibitor reduced the growth of human TNBC xenograft tumors. [ 43 ] Interestingly, metabolism-associated chromatin acetylation has been identified as a driver of the aggressive metastatic biology of TNBC. [ 44 ] The promoter of ANGPTL4 is acetylated and its acetylation corresponded with hypertriglyceridemia in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-like protein 4 is a chromatin-bound protein that enhances mammosphere formation in vitro and experimental triple-negative breast cancer brain and liver metastases in vivo

Simeon¹,

Thrush²,

Bailey³

2021

J Carcinog

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INTRODUCTION: Metastatic progression in triple-negative breast cancer (TNBC) patients occurs primarily because of nuclear reprogramming that includes chromatin remodeling and epigenetic modifications. The existing and most successful chemotherapies available for metastatic TNBC target nuclear proteins or damage DNA. The objectives here are to investigate an undescribed role for the molecular biology of nuclear angiopoietin-like protein 4 (ANGPTL4) and to characterize the effect of ectopic overexpression of ANGPTL4 in the metastatic biology of TNBC. MATERIALS AND METHODS: Lentiviral-mediated transduction was used to overexpress ANGPTL4 in the TNBC cell line MD Anderson–metastatic breast cancer 231. The overexpression of ANGPTL4 was confirmed by western blot and ELISA. Subcellular fractionation, western blot, and immunofluorescence microscopy were used to characterize the intracellular localization of ANGPTL4. Mammosphere culture and the anchorage-independent growth assay analyzed the metastatic potential of the cell line. Xenograft assays assessed the effect of ANGPTL4 overexpression on TNBC metastases in vivo . RESULTS: The ANGPTL4 overexpressing cell line formed larger mammospheres and anchorage-independent colonies in vitro and developed larger primary tumors, more liver metastases, and brain metastatic outgrowth in vivo in comparison to a cell line that expressed endogenous levels of ANGPTL4. ANGPTL4, aurora kinase A (AURKA), a mitotic kinase, and Tat-interacting protein p60 kDa (Tip60), a lysine acetyltransferase, associated with chromatin in the ANGPTL4 overexpressing cells but not in cells that expressed endogenous levels of ANGPTL4. CONCLUSIONS: The ANGPTL4 overexpressing cell line showed in vitro and in vivo activities that suggest that nuclear ANGPTL4, AURKA, and Tip60 may cooperatively modulate TNBC metastases within chromatin-remodeling complexes or DNA-associated machinery.

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Section: Discussionmentioning

confidence: 99%

Angiopoietin-like protein 4 is a chromatin-bound protein that enhances mammosphere formation in vitro and experimental triple-negative breast cancer brain and liver metastases in vivo

Simeon¹,

Thrush²,

Bailey³

2021

J Carcinog

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“…As such, HAT inhibitors are in preclinical development, with early studies suggesting activity in preclinical breast cancer models. The Tip60 inhibitor TH1834 induces apoptosis by generating non-repairable DNA damage and elevated H4K8ac [82] in HRpositive MCF7 breast cancer cells and slows xenograft growth in vivo [83]. Another Tip60 inhibitor, garcinol, inhibits estradiol-induced cell proliferation by enhancing G0/G1 cell cycle arrest and increasing apoptosis in MCF7 cells [84].…”

Section: Hat-mediated Regulation Of the Dna Damage Responsementioning

confidence: 99%

Emerging Role of Epigenetic Modifiers in Breast Cancer Pathogenesis and Therapeutic Response

Lee

Sad

Fawwal

et al. 2023

Cancers

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Breast cancer pathogenesis, treatment, and patient outcomes are shaped by tumor-intrinsic genomic alterations that divide breast tumors into molecular subtypes. These molecular subtypes often dictate viable therapeutic interventions and, ultimately, patient outcomes. However, heterogeneity in therapeutic response may be a result of underlying epigenetic features that may further stratify breast cancer patient outcomes. In this review, we examine non-genetic mechanisms that drive functional changes to chromatin in breast cancer to contribute to cell and tumor fitness and highlight how epigenetic activity may inform the therapeutic response. We conclude by providing perspectives on the future of therapeutic targeting of epigenetic enzymes, an approach that holds untapped potential to improve breast cancer patient outcomes.

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“…WM-3835 has antitumor activity and potently inhibits the growth of osteosarcoma xenografts in mice ( 216 ). TH1834 dihydrochloride is a specific Tip60 (KAT5) histone acetyltransferase inhibitor ( 215 ). TH1834 dihydrochloride induces apoptosis and increases DNA damage in breast cancer cells.…”

Section: Acetylation System-based Targeted Drugs In Cancermentioning

confidence: 99%

“…TH1834 dihydrochloride does not affect the activity of the related histone acetyltransferase MOF. Anticancer activity ( 215 ). Combination therapy of CK1 inhibitor SR3029 and Tip60 inhibitor MG149 had stronger inhibitory effects on β-catenin acetylation, transcription of Wnt target genes, and viability and proliferation of colon cancer cells ( 214 ).…”

Section: Acetylation System-based Targeted Drugs In Cancermentioning

confidence: 99%

The role of protein acetylation in carcinogenesis and targeted drug discovery

2022

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Protein acetylation is a reversible post-translational modification, and is involved in many biological processes in cells, such as transcriptional regulation, DNA damage repair, and energy metabolism, which is an important molecular event and is associated with a wide range of diseases such as cancers. Protein acetylation is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) in homeostasis. The abnormal acetylation level might lead to the occurrence and deterioration of a cancer, and is closely related to various pathophysiological characteristics of a cancer, such as malignant phenotypes, and promotes cancer cells to adapt to tumor microenvironment. Therapeutic modalities targeting protein acetylation are a potential therapeutic strategy. This article discussed the roles of protein acetylation in tumor pathology and therapeutic drugs targeting protein acetylation, which offers the contributions of protein acetylation in clarification of carcinogenesis, and discovery of therapeutic drugs for cancers, and lays the foundation for precision medicine in oncology.

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TIP60 Inhibitor TH1834 Reduces Breast Cancer Progression in Xenografts in Mice

Cited by 14 publications

References 7 publications

Angiopoietin-like protein 4 is a chromatin-bound protein that enhances mammosphere formation in vitro and experimental triple-negative breast cancer brain and liver metastases in vivo

Angiopoietin-like protein 4 is a chromatin-bound protein that enhances mammosphere formation in vitro and experimental triple-negative breast cancer brain and liver metastases in vivo

Emerging Role of Epigenetic Modifiers in Breast Cancer Pathogenesis and Therapeutic Response

The role of protein acetylation in carcinogenesis and targeted drug discovery

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