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ACK1/TNK2 Epigenetically Regulates Cell Cycle Program to Promote Breast Cancer Resistance to CDK4/6 inhibitor (ChIP-Seq)

ABSTRACT: Over-activation of oncogenes by aberrant expression of epigenetic modulators, overcoming cell cycle checkpoints and bestowing infinite multiplication potency acts as the mainstay of malignancy. We identified one such non-receptor tyrosine kinase ACK1 as an epigenetic regulator of cell cycle genes governing the G2/M transition of breast cancer cells. ACK1 was found to be over-activated (pY264-ACK1) in most of the breast cancer sub-types, independent of their hormone receptor status, as assessed by the Tissue-microarray analysis of nearly 400 breast cancer patient samples. ACK1 primed the epigenetic landscape surrounding the genes CCNB1, CCNB2 and CDC20 by depositing Y88-H4 histone activation marks, in turn initiating their efficient transcription. Pharmacological inhibition of ACK1 using small molecular inhibitor (R)-9b not only reversed this transcriptional potential but also sensitized the cells to a G2/M arrest, culminating in breast cancer cell death and tumor regression in in vivo xenograft models of breast cancer. Further, ACK1 was also found to modulate expression of the gene CXCR4, circumventing breast cancer metastasis on ACK1 ablation. In addition, ACK1 inhibition was also found to counteract the resistance of RB1 deficient breast cancer cells to the CDK4/6 inhibitor palbociclib, overcoming road blocks to conventional therapeutics. Overall, our data warrants the identification of ACK1 as an epigenetic controller of genes essential for the successful establishment and progression of breast cancer and signifies development of therapeutics against ACK1 to combat intrinsic and acquired breast cancer resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203230 | GEO | 2023/05/23

REPOSITORIES: GEO

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ACK1/TNK2 Epigenetically Regulates Cell Cycle Program to Promote Breast Cancer Resistance to CDK4/6 inhibitor (RNA-Seq)

Project description:Over-activation of oncogenes by aberrant expression of epigenetic modulators, overcoming cell cycle checkpoints and bestowing infinite multiplication potency acts as the mainstay of malignancy. We identified one such non-receptor tyrosine kinase ACK1 as an epigenetic regulator of cell cycle genes governing the G2/M transition of breast cancer cells. ACK1 was found to be over-activated (pY264-ACK1) in most of the breast cancer sub-types, independent of their hormone receptor status, as assessed by the Tissue-microarray analysis of nearly 400 breast cancer patient samples. ACK1 primed the epigenetic landscape surrounding the genes CCNB1, CCNB2 and CDC20 by depositing Y88-H4 histone activation marks, in turn initiating their efficient transcription. Pharmacological inhibition of ACK1 using small molecular inhibitor (R)-9b not only reversed this transcriptional potential but also sensitized the cells to a G2/M arrest, culminating in breast cancer cell death and tumor regression in in vivo xenograft models of breast cancer. Further, ACK1 was also found to modulate expression of the gene CXCR4, circumventing breast cancer metastasis on ACK1 ablation. In addition, ACK1 inhibition was also found to counteract the resistance of RB1 deficient breast cancer cells to the CDK4/6 inhibitor palbociclib, overcoming road blocks to conventional therapeutics. Overall, our data warrants the identification of ACK1 as an epigenetic controller of genes essential for the successful establishment and progression of breast cancer and signifies development of therapeutics against ACK1 to combat intrinsic and acquired breast cancer resistance.

2023-05-23 | GSE203231 | GEO

T Cell Reinvigoration upon ACK1/TNK2 inhibition Overcomes Immune Resistance

Project description:Solid tumors are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of the effector T cells and its trafficking back to the tumor. The T cell activation is negatively regulated by C-terminal Src kinase (CSK), however, the exact mechanism of CSK’s T cell-restraining activity remains unknown. Here, we show that the primeval oncogenic tyrosine kinase, ACK1 dampens T-cell response by augmenting CSK activity through a novel Tyr18-phosphorylation. Ack1/Tnk2-knockout mice exhibited a loss of CSK Tyr18-phosphorylation and activation of CD8+ and CD4+ T cells, compromising ICB-resistant tumor growth. Further, ICB-treated Castration-resistant prostate cancer (CRPC) patients revitalized ACK1/pY18-CSK signaling, revealing it to be the critical molecular mechanism for ICB insensitivity. Consistently, ICB-resistant tumor growth was suppressed upon treatment with a new class of ACK1 small-molecule inhibitor, (R)-9b. Interestingly, (R)-9b caused increase in leukocyte attractant, CXCL10 in cancer cells, thus navigating newly activated T cells to the tumors, creating a `self-sabotaging loop’. Overall, harnessing unique dichotomous mode of ACK1 that controls immune response of the T cells, and cytokine levels in tumor microenvironment, provides an unprecedented opportunity to sensitize immune-resistance.

2022-09-01 | GSE211835 | GEO

Chronologically Modified Androgen Receptor in Recurrent Castration Resistant Prostate Cancer and its therapeutic targeting

Project description:We uncovered a novel acetylation event at Lys609 in the Zinc finger DNA binding domain of AR (acK609-AR) that altered global transcription program, bestowing insensitivity for enzalutamide and abiraterone. ACK1 kinase small molecule inhibitor, (R)-9b not only curbed K609-acetylation, but also significantly compromised enzalutamide-resistant CRPC tumor growth.

2021-06-01 | GSE162761 | GEO

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance

Project description:Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK pY18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.

2023-03-11 | PXD037546 | Pride

Targeted Escalation of Tyrosine Kinase Super-Enhancer Network Engineered by Acetylated HOXB13 Spurs Prostate Tumor Autonomy

Project description:While tissue and lineage-specific super-enhancers (SEs) regulate cell fate decision during development, the nature of Castration Resistant Prostate Cancer (CRPC)-specific SEs (CSEs) is unknown. Herein we report the lysine 13 (K13) acetylation of HOXB13 mediated by the histone acetyltransferase CBP/p300 regulates prostate tumor autonomy. The acK13-HOXB13 shadows H3K27ac at lineage specific SEs and surpasses it at CSEs. In contrast, mutation of HOXB13 at K13 sensitizes CRPCs to Enzalutamide, disables spheroid and xenograft tumor formation. Mechanistically, the acK13-HOXB13 interacts with chromatin remodeling bromodomain proteins to regulate tumor-specific CSE selection. These CSEs sprout at critical lineage genes NKX3-1, Androgen receptor (AR), AR regulator ACK1 tyrosine kinase and tyrosine kinase ligands regulating angiogenesis. Single-cell transcriptomic analysis of human prostate tumor organoids reveal ACK1 expression underlies sensitivity to the small molecule inhibitor (R)-9b over AR-targeted agents. Collectively, our studies reveal acK13-HOXB13 regulated epigenome as a key cog in prostate cancer cell autonomy.

2022-09-22 | GSE167506 | GEO

Epigenetic Reprogramming of Androgen Receptor by Histone H4 Tyr88-phosphorylation Promotes Castration Resistance

Project description:Androgen receptor (AR) is critical for the progression of prostate cancer to the castration resistant (CRPC) state. Despite initial response, AR antagonists are ineffective long term in stifling AR activity due to their inability to repress expression of the AR or its splice variant, AR-V7. Here, we report that ACK1 tyrosine kinase, frequently deregulated in CRPCs, phosphorylates histone H4 at tyrosine 88, upstream of the AR transcription start site. WDR5/MLL2 complex reads the H4Y88 marks and modifies H3 in trans to deposit the transcriptionally activating H3K4 trimethyl marks, promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by ACK1 small molecule inhibitor, (R)-9bMS, sensitized naïve and enzalutamide-resistant cancer cells, repressed AR and AR-V7 levels to mitigate in vivo CRPC tumor growth. Thus, a feed-forward ACK1-H4-WDR5/MLL2-AR/AR-V7 epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.

2017-03-01 | GSE79689 | GEO

Gene expression analysis of breast cancer (HCC1954) and normal breast cells (HMEC)

Project description:While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors as well as changes in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe the first complete methylome maps at single nucleotide resolution of a low-passage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive and complementary relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells and suggesting a possible new approach toward the development of cancer therapeutics. mRNA-Seq of polyA-selected RNA from breast cancer HCC1954 and normal breast HMEC. 36 cycles of sequencing on Illumina platform.

2011-09-16 | E-GEOD-29119 | biostudies-arrayexpress

Bisulfite sequencing of ChIP DNA on breast cancer cells (HCC1954)

Project description:While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors as well as changes in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe the first complete methylome maps at single nucleotide resolution of a low-passage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive and complementary relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells and suggesting a possible new approach toward the development of cancer therapeutics. ChIP-methylC-Seq on H3K9me3, H3K27me3, and H3K36me3 in breast cancer HCC1954. 36 cycles of sequencing on Illumina platform.

2011-09-16 | E-GEOD-29120 | biostudies-arrayexpress

Histone PTM profiling during the cell cycle

Project description:To investigate how histone post-translational modifications (PTMs) change during the cell cycle, we profiled histone H3 and histone H4 in breast cancer and normal breast cell lines arrested in G1/S or G2/M phases.

2019-09-09 | PXD013288 | Pride

SHP2 as a Primordial Epigenetic Enzyme Expunges Histone H3 pTyr-54 to Amend Androgen Receptor Homeostasis

Project description:Mutations that decrease activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), causes Noonan syndrome with multiple lentigines or NSML (also called LEOPARD syndrome), while the gain-of-function mutations promotes several malignancies. Precisely how a spectrum of maladies ranging from developmental disorders to cancer are regulated by varying a solitary phosphatase activity is not clearly understood. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR and its target genes. The SANT domain of NCOR was identified as the epigenetic reader for pY54-H3 marks. NSML patients, SHP2 knock-in mice (which develops NSML), as well as ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation promoting tumor growth in prostate cancer patients.

2023-09-28 | GSE214870 | GEO

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