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Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy.

ABSTRACT: Tumor suppressor genes and oncogenes are both commonly altered during carcinogenesis. For oncogenes and other genes that drive growth, targeting mutated or activated forms (such as the EGFR-Her2/Nneu pathway) has been shown to be an effective anti-cancer approach. Pharmacologically targeting tumor suppressor genes has not been as fruitful, as many tumor suppressor genes are irreversibly silenced through somatic mutation or entirely deleted during carcinogenesis, thereby making it difficult to restore gene function. BRM, a key SWI/SNF complex subunit and a putative tumor suppressor gene, is inactivated in 15-20% of many solid tumor types. Unlike other tumor suppressor genes, the loss of BRM has been shown to be a reversible epigenetic change, rather than an irreversible genetic alteration. Using a high throughput drug screen, we identified a number of compounds that could effectively restore BRM expression and function. Two of these compounds, RH (RH02032) and GK (GK0037), were found to be such reactivating agents. Both compounds led to robust re-expression of BRM, induced downstream expression of BRM-dependent genes and inhibited BRM-dependent growth across a wide range of BRM-deficient cancer cell lines of different origins. We therefore show, for the first time, that pharmacologic reversal of epigenetic changes of the SWI/SNF chromatic remodeling complex subunit, BRM, is a potentially viable and novel therapeutic approach.

SUBMITTER: Gramling S

PROVIDER: S-EPMC3402205 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy.

Gramling S S Rogers C C Liu G G Reisman D D

Oncogene 20110411 29

Tumor suppressor genes and oncogenes are both commonly altered during carcinogenesis. For oncogenes and other genes that drive growth, targeting mutated or activated forms (such as the EGFR-Her2/Nneu pathway) has been shown to be an effective anti-cancer approach. Pharmacologically targeting tumor suppressor genes has not been as fruitful, as many tumor suppressor genes are irreversibly silenced through somatic mutation or entirely deleted during carcinogenesis, thereby making it difficult to re ...[more]

PMID: 21478905

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Project description:IntroductionDNA methylation-induced silencing of genes encoding tumor suppressors is common in many types of cancer, but little is known about how such epigenetic silencing can contribute to tumor metastasis. The PRKD1 gene encodes protein kinase D1 (PKD1), a serine/threonine kinase that is expressed in cells of the normal mammary gland, where it maintains the epithelial phenotype by preventing epithelial-to-mesenchymal transition.MethodsThe status of PRKD1 promoter methylation was analyzed by reduced representation bisulfite deep sequencing, methylation-specific PCR (MSP-PCR) and in situ MSP-PCR in invasive and noninvasive breast cancer lines, as well as in humans in 34 cases of "normal" tissue, 22 cases of ductal carcinoma in situ, 22 cases of estrogen receptor positive, HER2-negative (ER+/HER2-) invasive lobular carcinoma, 43 cases of ER+/HER2- invasive ductal carcinoma (IDC), 93 cases of HER2+ IDC and 96 cases of triple-negative IDC. A reexpression strategy using the DNA methyltransferase inhibitor decitabine was used in vitro in MDA-MB-231 cells as well as in vivo in a tumor xenograft model and measured by RT-PCR, immunoblotting and immunohistochemistry. The effect of PKD1 reexpression on cell invasion was analyzed in vitro by transwell invasion assay. Tumor growth and metastasis were monitored in vivo using the IVIS Spectrum Pre-clinical In Vivo Imaging System.ResultsHerein we show that the gene promoter of PRKD1 is aberrantly methylated and silenced in its expression in invasive breast cancer cells and during breast tumor progression, increasing with the aggressiveness of tumors. Using an animal model, we show that reversion of PRKD1 promoter methylation with the DNA methyltransferase inhibitor decitabine restores PKD1 expression and blocks tumor spread and metastasis to the lung in a PKD1-dependent fashion.ConclusionsOur data suggest that the status of epigenetic regulation of the PRKD1 promoter can provide valid information on the invasiveness of breast tumors and therefore could serve as an early diagnostic marker. Moreover, targeted upregulation of PKD1 expression may be used as a therapeutic approach to reverse the invasive phenotype of breast cancer cells.

Project description:Integration of the proviral DNA intermediate into the host cell genome normally represents an essential step in the retroviral life cycle. While the reason(s) for this requirement remains unclear, it is known that unintegrated proviral DNA is epigenetically silenced. Here, we demonstrate that human immunodeficiency virus 1 (HIV-1) mutants lacking a functional integrase (IN) can mount a robust, spreading infection in cells expressing the Tax transcription factor encoded by human T-cell leukemia virus 1 (HTLV-1). In these cells, HIV-1 forms episomal DNA circles, analogous to hepatitis B virus (HBV) covalently closed circular DNAs (cccDNAs), that are transcriptionally active and fully capable of supporting viral replication. In the presence of Tax, induced NF-κB proteins are recruited to the long terminal repeat (LTR) promoters present on unintegrated HIV-1 DNA, and this recruitment in turn correlates with the loss of inhibitory epigenetic marks and the acquisition of activating marks on histones bound to viral DNA. Therefore, HIV-1 is capable of replication in the absence of integrase function if the epigenetic silencing of unintegrated viral DNA can be prevented or reversed.IMPORTANCE While retroviral DNA is synthesized normally after infection by integrase-deficient viruses, the resultant episomal DNA is then epigenetically silenced. Here, we show that expression of the Tax transcription factor encoded by a second human retrovirus, HTLV-1, prevents or reverses the epigenetic silencing of unintegrated HIV-1 DNA and instead induces the addition of activating epigenetic marks and the recruitment of NF-κB/Rel proteins to the HIV-1 LTR promoter. Moreover, in the presence of Tax, the HIV-1 DNA circles that form in the absence of integrase function are not only efficiently transcribed but also support a spreading, pathogenic integrase-deficient (IN-) HIV-1 infection. Thus, retroviruses have the potential to replicate without integration, as is indeed seen with HBV. Moreover, these data suggest that integrase inhibitors may be less effective in the treatment of HIV-1 infections in individuals who are also coinfected with HTLV-1.

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Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy.

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Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy.

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