The role of 5′ untranslated region in translational suppression of OKL38 mRNA in hepatocellular carcinoma

Ong, Choon‐Kiat; Leong, Caine; Tan, Puay‐Hoon; Văn, Tạ Thành; Huynh, Hung

doi:10.1038/sj.onc.1209896

Cited by 17 publications

(19 citation statements)

References 22 publications

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“…The expression of OKL38 is normally induced during pregnancy and lactation in the rat mammary gland, which was proposed to contribute to the cell growth arrest and terminal cell differentiation (30). The loss or decrease of OKL38 protein has been reported in over 60% of hepatocellular carcinoma (26), suggesting that OKL38 may function as a tumor suppressor. How cancer cells gained growth advantage after the loss of OKL38 expression as well as how OKL38 induces cytochrome c release await future investigation.…”

Section: Discussionmentioning

confidence: 99%

“…To analyze the effects of PAD4 inhibition by Cl-amidine on global gene expression, microarray analyses were performed using MCF-7 cells treated with 200 M Cl-amidine for 24 h. One of the genes activated by Cl-amidine, pregnancy-induced growth inhibitor/ OKL38/BDGI, was previously reported to play a role in cell growth inhibition and tumorigenesis (26,27,30). To further test the induction of OKL38 by Cl-amidine, mRNA from MCF-7 cells treated with or without Cl-amidine was analyzed by quantitative reverse transcription-PCR (qRT-PCR).…”

Section: Pad4mentioning

confidence: 99%

“…Here we report that the expression of a putative tumor suppressor gene, OKL38/BDGI (26,27), was significantly induced by Cl-amidine treatment in several cancer cell lines. Bioinformatic and electrical mobility shift analyses identified a putative p53-binding site at the promoter of OKL38.…”

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confidence: 90%

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Histone Arg Modifications and p53 Regulate the Expression of OKL38, a Mediator of Apoptosis

Yao

Venters

et al. 2008

Journal of Biological Chemistry

137

139

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Protein Arg methyltransferases function as coactivators of the tumor suppressor p53 to regulate gene expression. Peptidylarginine deiminase 4 (PAD4/PADI4) counteracts the functions of protein Arg methyltransferases in gene regulation by deimination and demethylimination. Here we show that the expression of a tumor suppressor gene, OKL38, is activated by the inhibition of PAD4 or the activation of p53 following DNA damage. Chromatin immunoprecipitation assays showed a dynamic change of p53 and PAD4 occupancy and histone Arg modifications at the OKL38 promoter during DNA damage, suggesting a direct role of PAD4 and p53 in the expression of OKL38. Furthermore, we found that OKL38 induces apoptosis through localization to mitochondria and induction of cytochrome c release. Together, our studies identify OKL38 as a novel p53 target gene that is regulated by PAD4 and plays a role in apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Pad4mentioning

confidence: 99%

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Histone Arg Modifications and p53 Regulate the Expression of OKL38, a Mediator of Apoptosis

Yao

Venters

et al. 2008

Journal of Biological Chemistry

137

139

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“…Forced expression of OKL38 has been correlated with cell growth inhibition and apoptosis induction in multiple cell types [23], [26], [27]. Conversely, the loss or decreased expression of OKL38 protein has been detected in a high percentage of liver and kidney tumors [28], [29]. Thus, OKL38 likely plays a critical role in multiple tissues to guard against tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Interaction of OKL38 and p53 in Regulating Mitochondrial Structure and Function

Yao

Gan

et al. 2012

PLoS ONE

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The tumor suppressor p53 is a well-known transcription factor controlling the expression of its target genes involved in cell cycle and apoptosis. In addition, p53 also plays a direct proapoptotic role in mitochondria by regulating cytochrome c release. Recently, we identified a novel downstream target of p53, OKL38, which relocalizes from nucleus to mitochondria upon forced expression to induce apoptosis. However, the mechanism underlying OKL38 targeting to mitochondria and apoptosis induction remains unclear. Here, we found that OKL38 interacts with p53 to regulate mitochondria function. After DNA damage, OKL38 colocalizes with p53 to mitochondria in U2OS cells. Further, p53 and OKL38 are targeted to mitochondria in synergy: forced expression of OKL38 leads to p53 localization to mitochondria while the expression of a mitochondria enriched p53 polymorphic variant, p53R72, leads to OKL38 enrichment in mitochondria. Biochemical analyses found that OKL38 and p53 interact in vivo and in vitro via multiple domains. In cell biological assays, multiple regions of OKL38 mediate its mitochondria localization and induce mitochondria morphology changes. OKL38 induces formation of megamitochondria and increases cellular levels of reactive oxygen species. Furthermore, OKL38 induces cytochrome c release upon incubation with mitochondria. Taken together, our studies suggest that OKL38 regulates mitochondria morphology and functions during apoptosis together with p53.

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“…Promoters represent an important reservoir of biological, functional, and regulatory diversity, as current estimates suggest that 30% to 50% of genes in the human genome are associated with multiple promoters (15), which can be selectively activated as a function of developmental lineage and cellular state (16). Differential usage of alternative promoters causes the generation of distinct 5′ untranslated regions (5′ UTR) and first exons in transcripts, which in turn can influence mRNA expression levels (17), translational efficiencies (18,19), and the generation of different protein isoforms through gain and loss of 5′ coding domains (15,20). In cancer, alternative promoters in genes such as ALK (21), TP53 (22), LEF1 (23), and CYP19A1 (24) have been reported, producing cancer-specific isoform variants with oncogenic properties.…”

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confidence: 99%

Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma

et al. 2017

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Promoter elements play important roles in isoform and cell type-specific expression. We surveyed the epigenomic promoter landscape of gastric adenocarcinoma, analyzing 110 chromatin profiles (H3K4me3, H3K4me1, H3K27ac) of primary gastric cancers, gastric cancer lines, and nonmalignant gastric tissues. We identified nearly 2,000 promoter alterations (somatic promoters), many deregulated in various epithelial malignancies and mapping frequently to alternative promoters within the same gene, generating potential pro-oncogenic isoforms (RASA3). Somatic promoterassociated N-terminal peptides displaying relative depletion in tumors exhibited high-affinity MHC binding predictions and elicited potent T-cell responses in vitro, suggesting a mechanism for reducing tumor antigenicity. In multiple patient cohorts, gastric cancers with high somatic promoter usage also displayed reduced T-cell cytolytic marker expression. Somatic promoters are enriched in PRC2 occupancy, display sensitivity to EZH2 therapeutic inhibition, and are associated with novel cancer-associated transcripts. By generating tumor-specific isoforms and decreasing tumor antigenicity, epigenomic promoter alterations may thus drive intrinsic tumorigenesis and also allow nascent cancers to evade host immunity. SIGNIFICANCE:We apply epigenomic profiling to demarcate the promoter landscape of gastric cancer. Many tumor-specific promoters activate different promoters in the same gene, some generating pro-oncogenic isoforms. Tumor-specific promoters also reduce tumor antigenicity by causing relative depletion of immunogenic peptides, contributing to cancer immunoediting and allowing tumors to evade host immune attack. Cancer Discov; 7(6);

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The role of 5′ untranslated region in translational suppression of OKL38 mRNA in hepatocellular carcinoma

Cited by 17 publications

References 22 publications

Histone Arg Modifications and p53 Regulate the Expression of OKL38, a Mediator of Apoptosis

Histone Arg Modifications and p53 Regulate the Expression of OKL38, a Mediator of Apoptosis

Interaction of OKL38 and p53 in Regulating Mitochondrial Structure and Function

Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma

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