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Valproic acid achieves its anticancer activity by re-expression of cyclin D2

ABSTRACT: In this study we could show that the treatment of primary murine prostate cancer(PCa) cells derived from the well-established TRAMP (transgenic adenocarcinoma ofmouse prostate) model with the histone deacetylase inhibitor (HDI) valproic acid (VPA) has an anti-proliferative, anti-migrative and anti-invasive effect on the cells.To our knowledge this is the first study that identified that treatment of PCa cells with VPA leads to the re-expression of cyclin D2, which is known to be frequently inactive in patients with PCa. Additionally, we could demonstrate that VPA specifically induces re-expression of cyclin D2 as a family member of the highly conserved Dtype cyclins in human colorectal and mammary gland adenocarcinoma cell lines, whereas VPA treatment has no effect in NIH/3T3 fibroblasts. The observed cyclin D2 re-expression in cancer cells is activated by an increase of histone acetylation in the promoter region of the cyclin D2 gene and might be the underlying molecular mechanism of the inhibition of proliferation of cancer cells after VPA treatment. Taken together, our results confirm VPA as an anticancer therapeutic option in tumors with epigenetically repressed cyclin D2 expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE34072 | GEO | 2013/03/01

SECONDARY ACCESSION(S): PRJNA149995

REPOSITORIES: GEO

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Valproic acid achieves its anticancer activity by re-expression of cyclin D2

Project description:In this study we could show that the treatment of primary murine prostate cancer(PCa) cells derived from the well-established TRAMP (transgenic adenocarcinoma ofmouse prostate) model with the histone deacetylase inhibitor (HDI) valproic acid (VPA) has an anti-proliferative, anti-migrative and anti-invasive effect on the cells.To our knowledge this is the first study that identified that treatment of PCa cells with VPA leads to the re-expression of cyclin D2, which is known to be frequently inactive in patients with PCa. Additionally, we could demonstrate that VPA specifically induces re-expression of cyclin D2 as a family member of the highly conserved Dtype cyclins in human colorectal and mammary gland adenocarcinoma cell lines, whereas VPA treatment has no effect in NIH/3T3 fibroblasts. The observed cyclin D2 re-expression in cancer cells is activated by an increase of histone acetylation in the promoter region of the cyclin D2 gene and might be the underlying molecular mechanism of the inhibition of proliferation of cancer cells after VPA treatment. Taken together, our results confirm VPA as an anticancer therapeutic option in tumors with epigenetically repressed cyclin D2 expression. For the comparison of vpa treatment in murine protate cancer cells we hybridized 3 replicates per condition

2013-03-01 | E-GEOD-34072 | biostudies-arrayexpress

Sca-1 is an early-response target of histone deacetylase inhibitors and marks hematopoietic cells with enhanced function

Project description:Expression profiles of LSK cells stimulated for 24h in the presence or in the absence of of valproic acid (VPA) The molecular process that underlies the biological effects of valproic acid (VPA), a widely used histone deacetylase inhibitor, on HSPCs was investigated by studying the early-response genes of VPA. Genome-wide gene expression studies revealed overrepresentation of genes involved in glutathione metabolism, receptor and signal transducer activity and changes in the HSPCs surface profile following short, 24h VPA treatment. Sca-1, a well-known and widely used stem cell surface marker, was identified as a prominent VPA target.VPA strongly preserved Sca-1 expression on LSK cells, but also re-activated Sca-1 on committed progenitor cells that were Sca-1 negative, thereby reverting them to the LSK phenotype. We demonstrated that re-acquired Sca-1 expression coincided with induced self-renewal capacity as measured by in vitro re-plating assays, while Sca-1 itself was not required for the biological effects of VPA as demonstrated using Sca-1 deficient progenitor cells. We show that VPA can induce several genes involved in signal transduction of which Sca-1 was shown to mark cells with increased self-renewal capacity.

2012-09-25 | GSE41020 | GEO

Mus musculus

Project description:Valproic acid achieves its anticancer activity by re-expression of cyclin D2

| PRJNA149995 | ENA

Sca-1 is an early-response target of histone deacetylase inhibitors and marks hematopoietic cells with enhanced function

2012-09-25 | E-GEOD-41020 | biostudies-arrayexpress

Therapy-Induced Developmental Reprogramming of Prostate Cancer Cells and Acquired Resistance [Dataset 2]

Project description:Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). We propose that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) and showed that AR+/PSA+ PCa cell lines were efficiently reprogrammed to and maintained as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed CSCs overexpressed stem genes, had features of N/NC stem cells, high tumor-initiating potential, resistance to anti-androgen and an EMT phenotype. Serum-containing mediums allowed re-differentiation to N-/NC-derived cell lineages or return back to PCa-like cancer cells. Once returned, the cells had increased resistance to androgen signaling inhibition. Finally, a 62-gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. Gene expression profiles were obtained for RNAs extracted from biological replicates of parental LNCaP cells or from Neuroendocrine-like LNCaP (LNCaP-NE) cells grown for 15 days in CSS-media with no androgen.

2016-03-11 | E-GEOD-66851 | biostudies-arrayexpress

Therapy-Induced Developmental Reprogramming of Prostate Cancer Cells and Acquired Resistance [Dataset 1]

Project description:Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). We propose that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) and showed that AR+/PSA+ PCa cell lines were efficiently reprogrammed to and maintained as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed CSCs overexpressed stem genes, had features of N/NC stem cells, high tumor-initiating potential, resistance to anti-androgen and an EMT phenotype. Serum-containing mediums allowed re-differentiation to N-/NC-derived cell lineages or return back to PCa-like cancer cells. Once returned, the cells had increased resistance to androgen signaling inhibition. Finally, a 62-gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. To compare gene expression between parental PCa cells and STM-reprogrammed cells (LNCaP, VCaP, CWR-22rv1 and LAPC4), RNAs from biological triplicate samples of parental cells and corresponding STM-reprogrammed cells (>14 days in STM) were extracted.

2016-03-11 | E-GEOD-66850 | biostudies-arrayexpress

Chaperone-mediated autophagy promotes PCa survival during ARPI through selective proteome remodeling

Project description:Defining acute stress response mechanisms that mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with androgen receptor pathway inhibition (ARPI). ARPI causes abrupt environmental changes, subjecting PCa cells to acute metabolic stress. We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC). CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. As mediator of selective protein degradation, CMA orchestrates cellular pathway changes mediating the cellular stress response. Broad-spectrum proteomic analysis identified CMA induced proteome remodeling acutely after ARPI stress. CMA sustained PCa growth and survival during ARPI, promoting metabolic reprogramming through the upregulation mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. The upregulation of CMA promotes PCa cell proliferation after ARPI, and emergence of CRPC in-vivo. CMA inhibition compromised PCa metabolism, leading to ATP depletion and profound anti-proliferative effects on PCa cells, enhanced when combined with ARPI. CMA inhibition prevented in-vivo tumour formation, while also re-sensitizing enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. This study established CMA as an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress to promote PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa.

2023-01-26 | PXD036227 | Pride

Therapy-Induced Developmental Reprogramming of Prostate Cancer Cells and Acquired Resistance [Dataset 2]

Project description:Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.

2016-03-11 | GSE66851 | GEO

Therapy-Induced Developmental Reprogramming of Prostate Cancer Cells and Acquired Resistance [Dataset 1]

2016-03-11 | GSE66850 | GEO

A Window of Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker

Project description:Purpose: Valproic acid(VPA) has anti-cancer activity attributed to histone deacetylase inhibition(HDACi). We published the Genomically–Derived Sensitivity Signature for VPA(GDSS-VPA), a gene expression biomarker predicting breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study examining the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors from VPA. Methods: Eligible women had untreated breast cancer with breast tumors over 1.5 cm. After a biopsy, women took VPA for 7-12 days, increasing from 30mg/kg/day PO divided BID to a maximum of 50mg/kg/day. After VPA treatment, serum VPA level was measured followed by breast surgery or a biopsy. Tumor proliferation was assessed by Ki-67 immunohistochemistry. Peripheral blood mononuclear cells(PBMCs) histone acetylation was assessed by Western blot. Results: Thirty women were evaluable. The median age was 54(range 31-73). 52% of women tolerated 50mg/kg/day, but 10% missed more than two doses due to adverse events(AEs). Grade 3 AEs included one patient with vomiting and diarrhea and one with fatigue. The end serum VPA level correlated with change in PBMC histone acetylation(rho=0.451, p=0.024). 50% of women with triple-negative breast cancer(TNBC) had a Ki-67 reduction of at least 10%, compared with 17% of other women. GDSS-VPA correlated with a Ki-67 decrease of at least 10%(AUC 0.66). Conclusions: Most women tolerate VPA. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. HDACi is a valid strategy for drug development in TNBC using gene expression biomarkers.

2016-12-17 | GSE83530 | GEO

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