Epigenetics-targeted drugs: current paradigms and future challenges

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Ноя. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Язык: Английский

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MYCN and KAT2A form a feedforward loop to drive an oncogenic transcriptional program in neuroblastoma

Oncogenesis, Год журнала: 2025, Номер 14(1)

Опубликована: Апрель 24, 2025

Abstract The oncoprotein MYCN drives malignancy in various cancer types, including neuroblastoma (NB). However, our understanding of the mechanisms underlying its transcriptional activity and oncogenic function, as well effective strategies to target it, remains limited. We discovered that interacts with coactivator KAT2A, this interaction significantly contributes MYCN’s NB. Our genome-wide analyses indicate recruits KAT2A bind DNA, thereby transcriptionally regulating genes associated ribosome biogenesis RNA processing. Moreover, we identified directly activates transcription, while acetylates MYCN, increasing protein stability. Consequently, establish a feedforward loop effectively regulates global gene expression, governing malignant NB phenotype. Treatment cells Proteolysis Targeting Chimera (PROTAC) degrader reduces levels, antagonizes MYCN-mediated transcription regulation suppresses cell proliferation. This study highlights potential cofactors viable targets for developing anti-MYCN therapies.

Язык: Английский

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The SAGA acetyltransferase module is required for the maintenance of MAF and MYC oncogenic gene expression programs in multiple myeloma

Genes & Development, Год журнала: 2024, Номер 38(15-16), С. 738 - 754

Опубликована: Авг. 1, 2024

Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator transcription catalyzes acetylation deubiquitylation. Analyses of data sets Cancer Dependency Map Project revealed that many components are selective dependencies MM. To define SAGA-specific functions, we focused ADA2B, only subunit lysine acetyltransferase (KAT) module specifically functions SAGA. Integration RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with (ATAC-seq), cleavage under targets release using nuclease (CUT&RUN) results identified pathways directly regulated by ADA2B including MTORC1 signaling oncogenic programs driven MYC, E2F, MM-specific MAF. We discovered recruited MAF MYC gene targets, shares majority its cells. Furthermore, found SANT domain required interaction both GCN5 PCAF acetyltransferases, incorporation into SAGA, protein stability. Our findings uncover previously unknown KAT module-dependent controlling cell growth, revealing vulnerability might be exploited future therapy.

Язык: Английский

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KAT tales: Functions of Gcn5 and PCAF lysine acetyltransferases in SAGA and ATAC

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(10), С. 107744 - 107744

Опубликована: Сен. 1, 2024

Язык: Английский

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