Cyclin‐dependent kinase 9 (CDK9), a catalytic subunit of the positive transcription elongation factor b (P‐TEFb) complex, is a global transcriptional elongation factor associated with cell proliferation. CDK9 activity is regulated by certain histone acetyltransferases, such as p300, GCN5 and P/CAF. However, the impact of males absent on the first (MOF) (also known as KAT8 or MYST1) on CDK9 activity has not been reported. Therefore, the present study aimed to elucidate the regulatory role of MOF on CDK9. We present evidence from systematic biochemical assays and molecular biology approaches arguing that MOF interacts with and acetylates CDK9 at the lysine 35 (i.e. K35) site, and that this acetyl‐group can be removed by histone deacetylase HDAC1. Notably, MOF‐mediated acetylation of CDK9 at K35 promotes the formation of the P‐TEFb complex through stabilizing CDK9 protein and enhancing its association with cyclin T1, which further increases RNA polymerase II serine 2 residues levels and global transcription. Our study reveals for the first time that MOF promotes global transcription by acetylating CDK9, providing a new strategy for exploring the comprehensive mechanism of the MOF–CDK9 axis in cellular processes.

01 Mar 2023·European Journal of Medicinal Chemistry

Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells

Article

Author: Wang, Xuan ; Yang, Guang ; Wang, Jiefu ; Yang, Cheng ; Zhang, Li ; Li, Ming ; Zhang, Kun ; Wei, Mingming ; Liu, Yulin ; Sun, Yue ; Li, Xuechun ; Ma, Lan ; Wu, Yanjie ; Wei, Yujiao

Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.

01 Apr 2016·Nature Cell Biology

C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4

Article

Author: Lackner, Andreas ; Porse, Bo ; Mann, Matthias ; Stadhouders, Ralph ; Limone, Francesco ; Collombet, Samuel ; Graf, Thomas ; Wierer, Michael ; Jakobsen, Janus Schou ; Thieffry, Denis ; Francesconi, Mirko ; Di Stefano, Bruno ; Sardina, Jose Luis ; Segura-Morales, Carolina

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα.

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