Acetylation of C/EBPα inhibits its granulopoietic function

Bararia, Deepak; Kwok, Hui Si; Welner, Robert S.; Numata, Akihiko; Sárosi, Menyhárt B.; Yang, Henry; Wee, Sheena; Tschuri, Sebastian; Ray, Debleena; Weigert, Oliver; Ebralidze, Alexander K.; Gunaratne, Jayantha; Tenen, Daniel G.

doi:10.1038/ncomms10968

Cited by 40 publications

(42 citation statements)

References 62 publications

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“…1A). In agreement with a previous report (Bararia et al, 2016), Kat2a was dispensable for HSC maintenance and function, as assessed by BM composition acutely after excision and throughout aging ( Supplementary Fig. 1C-D), in vitro progenitor assays ( Supplementary Fig.…”

Section: Conditional Loss Of Kat2a Does Not Affect Normal Hematopoiessupporting

confidence: 93%

Loss of Kat2A Enhances Transcriptional Noise and Depletes Acute Myeloid Leukemia Stem-Like Cells

Domingues

Kulkarni

Giotopoulos

et al. 2018

Preprint

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Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective myelo-monocytic differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity, that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics, we demonstrate that Kat2a contributes to leukemia propagation through homogeneity of transcriptional programs and preservation of leukemia stem-like cells. Kat2a loss reduces transcriptional bursting frequency in a subset of gene promoters, generating enhanced variability of transcript levels but minimal effects on mean gene expression. Destabilization of target programs shifts cellular equilibrium out of selfrenewal towards differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and at distinct stages of cancer evolution.

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Section: Conditional Loss Of Kat2a Does Not Affect Normal Hematopoiessupporting

confidence: 93%

Loss of Kat2A Enhances Transcriptional Noise and Depletes Acute Myeloid Leukemia Stem-Like Cells

Domingues

Kulkarni

Giotopoulos

et al. 2018

Preprint

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“…23 NAMPT, together with its downstream effector molecule SIRT1, orchestrates neutrophil differentiation via activation of CEBPα and CEBPβ. 12 CEBPα and CEBPβ regulate in turn expression of many myeloid-specific genes, 24 and are essential for steady-state or emergency granulopoiesis. 25,26 Here, we observed a significant up-regulation of Nampt and Sirt1 in protumor TANs from Ifnar1 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

NAMPT signaling is critical for the proangiogenic activity of tumor‐associated neutrophils

Pylaeva

Harati

Spyra

et al. 2018

Intl Journal of Cancer

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Tumor-associated neutrophils (TANs) regulate many processes associated with tumor progression, and depending on the microenvironment, they can exhibit pro- or antitumor functions. However, the molecular mechanisms regulating their tumorigenicity are not clear. Using transplantable tumor models, we showed here that nicotinamide phosphoribosyltransferase (NAMPT), a molecule involved in CSF3R downstream signaling, is essential for tumorigenic conversion of TANs and their pro-angiogenic switch. As a result tumor vascularization and growth are strongly supported by these cells. Inhibition of NAMPT in TANs leads to their antitumor conversion. Adoptive transfer of such TANs into B16F10-tumor bearing mice attenuates tumor angiogenesis and growth. Of note, we observe that the regulation of NAMPT signaling in TANs, and its effect on the neutrophil tumorigenicity, are analogous in mice and human. NAMPT is up-regulated in TANs from melanoma and head-and-neck tumor patients, and its expression positively correlates with tumor stage. Mechanistically, we found that targeting of NAMPT suppresses neutrophil tumorigenicity by inhibiting SIRT1 signaling, thereby blocking transcription of pro-angiogenic genes. Based on these results, we propose that NAMPT regulatory axis is important for neutrophils to activate angiogenic switch during early stages of tumorigenesis. Thus, identification of NAMPT as the critical molecule priming protumor functions of neutrophils provides not only mechanistic insight into the regulation of neutrophil tumorigenicity, but also identifies a potential pathway that may be targeted therapeutically in neutrophils. This, in turn, may be utilized as a novel mode of cancer immunotherapy.

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“…Acetylation catalyzed by lysine acetyltransferases is another important post‐translational modification that plays a pivotal role in numerous cellular processes. GCN5 can interact with and acetylate C/EBPα on at least lysine K298 and K302 in the basic DNA binding domain (DBD), leading to impaired DNA binding activity and granulocytic differentiation capacity (Bararia et al , ). Interestingly, in the presence of hormone PR associated with C/EBPα also interacts with several acetyltransferases and HDACs (Fig EV4C and Vicent et al , , ) that could regulate its activity.…”

Section: Discussionmentioning

confidence: 99%

C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

et al. 2019

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Steroid hormones are key gene regulators in breast cancer cells. While estrogens stimulate cell proliferation, progestins activate a single cell cycle followed by proliferation arrest. Here, we use biochemical and genome‐wide approaches to show that progestins achieve this effect via a functional crosstalk with C/EBPα. Using ChIP‐seq, we identify around 1,000 sites where C/EBPα binding precedes and helps binding of progesterone receptor (PR) in response to hormone. These regions exhibit epigenetic marks of active enhancers, and C/EBPα maintains an open chromatin conformation that facilitates loading of ligand‐activated PR. Prior to hormone exposure, C/EBPα favors promoter–enhancer contacts that assure hormonal regulation of key genes involved in cell proliferation by facilitating binding of RAD21, YY1, and the Mediator complex. Knockdown of C/EBPα disrupts enhancer–promoter contacts and decreases the presence of these architectural proteins, highlighting its key role in 3D chromatin looping. Thus, C/EBPα fulfills a previously unknown function as a potential growth modulator in hormone‐dependent breast cancer.

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Acetylation of C/EBPα inhibits its granulopoietic function

Cited by 40 publications

References 62 publications

Loss of Kat2A Enhances Transcriptional Noise and Depletes Acute Myeloid Leukemia Stem-Like Cells

Loss of Kat2A Enhances Transcriptional Noise and Depletes Acute Myeloid Leukemia Stem-Like Cells

NAMPT signaling is critical for the proangiogenic activity of tumor‐associated neutrophils

C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

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