Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins

Nilsson, Lisa M.; Green, Lydia C.; Muralidharan, Somsundar Veppil; Demir, Dağsu; Welin, M.; Bhadury, Joydeep; Logan, D.T.; Walse, Björn; Nilsson, Jonas A.

doi:10.1158/0008-5472.can-15-2721

Cited by 14 publications

(17 citation statements)

References 26 publications

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“…These compounds inhibit the binding of BRD4 to its targets but also promote the release of P-TEFb from the inactive 7SK snRNP complex (Bartholomeeusen et al, 2012; Contreras et al, 2007; Filippakopoulos et al, 2010; Mirguet et al, 2013; Nilsson et al, 2016), thereby increasing the pool of SEC containing active P-TEFb (Figure 3D, Figure S3). As shown (Figure 3E–F, Figure S4), treatment of infected cells with JQ1+, HMBA, or IBET-762 results in enhanced IE gene mRNA levels in a manner analogous to depletion of BRD4.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency

Alfonso

Turner

Beltran

et al. 2017

Cell Host & Microbe

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Summary The cellular transcriptional coactivator HCF-1 is required for initiation of herpes simplex virus (HSV) lytic infection and for reactivation from latency in sensory neurons. HCF-1 stabilizes the viral Immediate Early (IE) genes enhancer complex and mediates chromatin transitions to promote IE transcription initiation. In infected cells, HCF-1 was also found to be associated with a network of transcription elongation components including the Super Elongation Complex (SEC). IE genes exhibit characteristics of genes controlled by transcriptional elongation and the SEC-P-TEFb complex is specifically required to drive the levels of productive IE mRNAs. Significantly, compounds that enhance the levels of SEC-P-TEFb also potently stimulated HSV reactivation from latency both in a sensory ganglia model system and in vivo. Thus, transcriptional elongation of HSV IE genes is a key limiting parameter governing both the initiation of HSV infection and reactivation of latent genomes.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency

Alfonso

Turner

Beltran

et al. 2017

Cell Host & Microbe

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“…Another chemical compound, HMBA, has been used to induce cancer cell differentiation for treating a number of cancers (43). The mechanism of HMBA action involves inducing the expression of the P-TEFb inhibitor HEXIM1 (41).…”

Section: Inhibition Of Brd4 Hyperphosphorylation By Chemical Compoundsmentioning

confidence: 99%

Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinoma

Wang

Cao

Kulej

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The epigenetic reader BRD4 plays a vital role in transcriptional regulation, cellular growth control, and cell-cycle progression. Dysregulation of BRD4 function has been implicated in the pathogenesis of a wide range of cancers. However, how BRD4 is regulated to maintain its normal function in healthy cells and how alteration of this process leads to cancer remain poorly understood. In this study, we discovered that BRD4 is hyperphosphorylated in NUT midline carcinoma and identified CDK9 as a potential kinase mediating BRD4 hyperphosphorylation. Disruption of BRD4 hyperphosphorylation using both chemical and molecular inhibitors led to the repression of BRD4 downstream oncogenes and abrogation of cellular transformation. BRD4 hyperphosphorylation is also observed in other cancers displaying enhanced BRD4 oncogenic activity. Our study revealed a mechanism that may regulate BRD4 biological function through phosphorylation, which, when dysregulated, could lead to oncogenesis. Our finding points to strategies to target the aberrant BRD4 signaling specifically for cancer intervention.

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“…We have previously published data demonstrating that BETis act as what historically was referred to cancer differentiating agents (6, 12). Tumor cell differentiation therapies held great promise during the 1980’s and 1990’s, but did not render any clinically approved therapies for solid tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas SAHA was found to inhibit histone deacetylases (HDACs) 1-3 and made it to clinical approval for cutaneous T-cell leukemia, HMBA neither inhibits HDACs nor received clinical approval, and its target was unknown for forty years (4, 5). Recently, however, we discovered that HMBA is a bromodomain and extra-terminal domain (BET) inhibitor, with highest binding affinity for bromodomain 2 (BD2) of BET proteins BRD2, BRD3 and BRD4 while also inhibiting the bromodomain of histone acetyltransferase P300 (6). The structure of HMBA largely resembles that of an acetylated lysine, explaining the mode of action.…”

Section: Introductionmentioning

confidence: 99%

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma

Funck‐Brentano

Vizlin‐Hodzic

Nilsson

et al. 2020

Preprint

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1) Background: BET bromodomain proteins regulate transcription by binding acetylated 8 histones and attracting key factors for e.g. transcriptional elongation. BET inhibitors have been 9 developed to block pathogenic processes such as cancer and inflammation. Despite having potent 10 biological activities, BET inhibitors have still not made a breakthrough in clinical use for treating 11 cancer. Multiple resistance mechanisms have been proposed but thus far no attempts to block this 12 in glioma has been made. (2) Methods: Here, we have conducted a pharmacological synergy screen 13 in glioma cells to search for possible combination treatments augmenting the apoptotic response to 14 BET inhibitors. We first used HMBA, a compound that was developed as a differentiation therapy 15 four decades ago but more recently was shown to primarily inhibit BET bromodomain proteins. 16Data was also generated using other BET inhibitors. (3) Results: In the synergy screen, we 17 discovered that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and 18 human glioma cells in vitro as well as in vivo xenografts. The combination is not unique to HMBA 19 but also other BET inhibitors such as JQ1 and I-BET-762 can synergize with MEK inhibitors. (4) 20 Conclusions: Our findings validate a combination therapy previously demonstrated to exhibit anti-21 cancer activities in multiple other tumor types but which appears to have been lost in translation to 22 the clinic.23 Keywords: BET bromodomain protein, hexamethylene bisacetamide, glioma 24 25 1. Introduction 26 Before the discovery of oncogenes the concept of cancer cell differentiation therapy was explored 27 therapeutically, in part based on early observations that dimethylsulfoxide (DMSO) can cause 28 differentiation of Friend virus induced mouse erythroleukemia (MEL) cells into hemoglobin 29producing red blood cells (1). Efforts to produce more potent cancer differentiation compounds 30 generated two molecules that were tested in the clinic, hexamethylene bisacetamide (HMBA) and 31 suberoylanilide hydroxamic acid (SAHA, later renamed to vorinostat) (2, 3). Whereas SAHA was 32 found to inhibit histone deacetylases (HDACs) 1-3 and made it to clinical approval for cutaneous T-33 cell leukemia, HMBA neither inhibits HDACs nor received clinical approval, and its target was 34 unknown for forty years (4, 5). Recently, however, we discovered that HMBA is a bromodomain and 35 extra-terminal domain (BET) inhibitor, with highest binding affinity for bromodomain 2 (BD2) of BET 36 proteins BRD2, BRD3 and BRD4 while also inhibiting the bromodomain of histone acetyltransferase 37 P300 (6). The structure of HMBA largely resembles that of an acetylated lysine, explaining the mode 38 of action. 40Although HMBA was likely the first anti-cancer compound used in the clinic that inhibited BET 41 bromodomain proteins, the concept of BET inhibitors (BETis) were largely popularized with the 42 development of the low nanomolar BETis JQ1 and iBET-151 (7, 8). The mechanism of action of thes...

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Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins

Cited by 14 publications

References 26 publications

Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency

Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency

Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinoma

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma

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