Transcriptional Regulation of Oncogenic Protein Kinase Cϵ (PKCϵ) by STAT1 and Sp1 Proteins

Wang, Hongbin; Gutiérrez-Uzquiza, Álvaro; Garg, Rachana; Barrio-Real, Laura; Abera, Mahlet B.; López‐Haber, Cynthia; Rosemblit, Cinthia; Lu, Huaisheng; Abba, Martı́n C.; Kazanietz, Marcelo G.

doi:10.1074/jbc.m114.548446

Cited by 31 publications

(20 citation statements)

References 68 publications

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“…To this end, we took advantage of a well-established model of experimental metastasis that uses PC3-ML human prostate cancer cells, a cell line with high bone metastatic potential derived from the PC3 parental cell line (25, 26). As previously reported for parental androgen-independent PC3 and DU145 cells (11, 23), the PC3-ML subline displays elevated levels of PKCε relative to “normal” immortalized prostate epithelial cells (Fig. 1a).…”

Section: Resultssupporting

confidence: 83%

PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

Gutiérrez-Uzquiza

López‐Haber

Jernigan

et al. 2015

Molecular Cancer Research

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The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced using shRNA. Interestingly, while PKCε depletion had only marginal effects on the proliferative, adhesive and migratory capacities of PC3-ML cells in vitro or in the growth of xenografts upon s.c. inoculation, it caused a significant reduction in cell invasiveness. Notably, PKCε was required for transendothelial cell migration (TEM) as well as for the growth of PC3-ML cells in a bone biomimetic environment. At a mechanistic level, PKCε depletion abrogates the expression of IL-1β, a cytokine implicated in skeletal metastasis. Taken together, PKCε is a key factor for driving the formation of bone metastasis by prostate cancer cells and is a potential therapeutic target for advanced stages of the disease. Implications This study uncovers an important new function of PKCε in the dissemination of cancer cells to the bone; thus, highlighting the promising potential of this oncogenic kinase as a therapeutic target for skeletal metastasis.

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Section: Resultssupporting

confidence: 83%

PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

Gutiérrez-Uzquiza

López‐Haber

Jernigan

et al. 2015

Molecular Cancer Research

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“…Since COX2 is a well-known NF-κB-regulated gene, we began with investigating if there is any association between PKCε and COX-2 expression in prostate cancer. As we previously reported ( 11 , 52 ), PKCε is highly expressed in androgen-independent prostate cancer cell lines (PC3, PC3-mL and DU145) compared to the androgen-dependent LNCaP, RWPE-1 (normal immortalized prostate epithelial) or RWPE-2 (Ras-transformed RWPE-1) cells. Up-regulated PKCε levels in aggressive prostate cancer cell lines correlate with both elevated COX-2 expression and nuclear translocation of NF-κB, a hallmark of NF-κB pathway activation ( Fig.…”

Section: Resultssupporting

confidence: 57%

COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer

et al. 2018

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The pro-oncogenic kinase PKCε is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE2 production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCε, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation as well as angiogenesis in a mouse model of prostate-specific PKCε expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-κB pathway and its target gene COX2 as PKCε effectors, and highlight the potential of PKCε as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer.

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“…However, many “hits” in this study with no readily apparent representation in the lung cancer methylome-related literature were found, [e.g., PR: DARS , CLDN18 , APIP; GB: ARHGEF12 PRKCE ], and are likely worthy of pursuit. The potential relevance of some of the unique DM genes identified here is described in Table 4i [ 41 – 46 ].…”

Section: Discussionmentioning

confidence: 99%

Genome Wide Methylome Alterations in Lung Cancer

Mullapudi

Suzuki

et al. 2015

PLoS ONE

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Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)–non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

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Transcriptional Regulation of Oncogenic Protein Kinase Cϵ (PKCϵ) by STAT1 and Sp1 Proteins

Cited by 31 publications

References 68 publications

PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer

Genome Wide Methylome Alterations in Lung Cancer

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