Upregulation of BNIP3 by 5-aza-2′-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death

Abe, Tomoki; Toyota, Minoru; Suzuki, Hiromu; Murai, Masafumi; Akino, Kimishige; Ueno, Masako; Nojima, Masanori; Yawata, Atsushi; Miyakawa, Hiroyoshi; Suga, Toshihiro; Ito, Hideto; Endo, Takao; Tokino, Takashi; Hinoda, Yuji; Imai, Kohzoh

doi:10.1007/s00535-005-1576-1

Cited by 62 publications

(46 citation statements)

References 31 publications

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“…Okami et al detected hypermethylation of the BNIP3 promoter in most of the BNIP3-silenced pancreatic cancer cell lines examined, including AsPC-1, Miapaca-2 and PANC-1 and in eight of ten primary pancreatic cancer tissues (Okami et al, 2004). Abe et al (2005) showed that BNIP3 promoter methylation was strong in the Miapaca-2, PK-8, PK-9 and PK-59 cell lines but weak in PANC-1 and CFPAC-1. For our study, we selected AsPC-1, Miapaca-2, PK-1 and PANC-1 for further investigation of BNIP3 promoter methylation and regulation of expression.…”

Section: Discussionmentioning

confidence: 99%

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Silencing of BNIP3 Results from Promoter Methylation by DNA Methyltransferase 1 Induced by the Mitogen-Activated Protein Kinase Pathway

Lee

Paik

2011

Molecules and Cells

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We have previously shown that Ras mediates NO-induced BNIP3 expression via the MEK-ERK-HIF-1 pathway in mouse macrophages, and that NO-induced death results at least in part from the induction of BNIP3. In the present study, we describe another aspect of Ras regulation of BNIP3 expression in pancreatic cancer cells. Human BNIP3 promoter-driven luciferase activity was efficiently induced by activated Ras in AsPC-1, Miapaca-2, PK-1 and PANC-1 cells. However, expression of endogenous BNIP3 was not induced, and BNIP3 up-regulation by hypoxia was also inhibited. Treatment of the cells with the DNMT inhibitor, 5-aza-2-deoxycytidine, restored BNIP3 induction, indicating that DNA methylation of the BNIP3 promoter was responsible for the inhibition of BNIP3 induction. Furthermore, inhibition of the MEK pathway with U0126 reduced DNMT1 expression, but not that of DNMT3a and 3b, and restored the hypoxia-inducibility of BNIP3, suggesting that the DNA methylation of the BNIP3 promoter was mediated by DNMT1 via the MEK pathway.

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Section: Discussionmentioning

confidence: 99%

“…The promoter of BNIP3 is located within a CpG island and is methylated in most pancreatic cancer cell lines (Abe et al, 2005;Akada et al, 2005;Erkan et al, 2005). Restoration of BNIP3 expression by the methyltransferase inhibitor, 5-aza-2-deoxycytidine, leads to the death of pancreatic cancer cells in response to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

Silencing of BNIP3 Results from Promoter Methylation by DNA Methyltransferase 1 Induced by the Mitogen-Activated Protein Kinase Pathway

Lee

Paik

2011

Molecules and Cells

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“…BNIP3 is one factor that has been found to be required to mediate autophagic cell death in response to hypoxia through HIF1a activities (Daido et al, 2004;Tracy et al, 2007a;Azad et al, 2008). The loss of BNIP3 in pancreatic and colon tumours, either by hypermethylation or by transcriptional repression, is correlated with inhibition of cell death (Okami et al, 2004;Murai et al, 2005;Bacon et al, 2007;Mahon et al, 2007), whereas up-regulation of BNIP3 sensitizes pancreatic carcinoma cells to hypoxia-induced cell death (Abe et al, 2005). Aleman et al (2005) have shown that cell death resulting from SIM2s antisense treatment of colon cancer RKO cells was apoptotic, being largely dependent on the activities of caspases 9 and 10; however, mechanisms of autophagy have not been investigated.…”

Section: Sim2s Attenuates Hypoxic Induction Of Bnip3 Via Activities Wmentioning

confidence: 99%

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Farrall

Whitelaw

2009

Oncogene

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The short isoform of single-minded 2 (SIM2s), a basic helix-loop-helix/PAS (bHLH/PAS) transcription factor, is upregulated in pancreatic and prostate tumours; however, a mechanistic role for SIM2s in these cancers is unknown. Microarray studies in prostate DU145 cells identified the pro-cell death gene, BNIP3 (Bcl-2/adenovirus E1B 19 kDa interacting protein 3), as a novel putative target of SIM2s repression. Further validation showed BNIP3 repression in several prostate and pancreatic carcinoma-derived cell lines with ectopic expression of human SIM2s. BNIP3 levels are enhanced in prostate carcinoma cells upon short interfering (si)RNA-mediated knockdown of endogenous SIM2s. Chromatin immunoprecipitation and promoter studies show that SIM2s represses BNIP3 through its activities at the proximal promoter hypoxia response element (HRE), the site through which the bHLH/PAS family member, hypoxia-inducible factor 1a (HIF1a), induces BNIP3. SIM2s attenuates BNIP3 hypoxic induction via the HRE, and increased hypoxic induction of BNIP3 occurs with siRNA knockdown of endogenous SIM2s in prostate PC3AR þ cells. BNIP3 is implicated in hypoxia-induced cell death processes. Prolonged treatment of PC3AR þ cells with hypoxia mimetics, DP and DMOG, confers hypoxia-induced autophagy, measured by enhanced LC3-II levels and SQSTM1/p62 turnover. We show that PC3AR þ cells expressing ectopic SIM2s have enhanced survival in these conditions. Induction of LC3-II and turnover of SQSTM1/p62 are attenuated in PC3AR þ / SIM2s DMOG and hypoxia-treated cells, suggesting that SIM2s may attenuate autophagic cell death processes, perhaps through BNIP3 repression. These data show, for the first time, SIM2s cross-talk on an endogenous HRE. SIM2s' functional interference with HIF1a activities on BNIP3 may indicate a novel role for SIM2s in promoting tumourigenesis.

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“…It is activated by HIF during hypoxia and initiates programmed cell death through apoptosis or autophagy (Ray et al, 2000;Mellor and Harris, 2007). Epigenetic silencing of BNIP3 by promoter hypermethylation has been reported in several cancer types and contributes to resistance to hypoxia-induced cell death (Okami et al, 2004;Abe et al, 2005;Yan et al, 2006). The role of BNIP3 in colorectal cancer (CRC) is unknown, although 66% tumours show BNIP3 silencing by promoter hypermethylation Bacon et al, 2007).…”

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confidence: 99%

Poorer outcome in stromal HIF-2α- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis

et al. 2008

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Stromal expression of hypoxia inducible factor 2a (HIF-2a) and carbonic anhydrase 9 (CA9) are associated with a poorer prognosis in colorectal cancer (CRC). Tumour cell death, regulated by a hypoxic stromal microenvironment, could be of importance in this respect. Therefore, we correlated apoptosis, TP53 mutational status and BNIP3 promoter hypermethylation of CRC cells with HIF-2a-and CA9-related poor outcome. In a series of 195 CRCs, TP53 mutations in exons 5 -8 were analysed by direct sequencing, and promoter hypermethylation of BNIP3 was determined by methylation-specific PCR. Expressions of HIF-2a, CA9, p53, BNIP3 and M30 were analysed immunohistochemically. Poorer survival of HIF-2a and CA9 stromal-positive CRCs was associated with wild-type TP53 (P ¼ 0.001 and P ¼ 0.0391), but not with BNIP3 methylation. Furthermore, apoptotic levels were independent of the TP53 status, but lower in unmethylated BNIP3 CRCs (P ¼ 0.004). It appears that wild-type TP53 in CRC cells favours the progression of tumours expressing markers for hypoxia in their stroma, rather than in the epithelial compartment. Preserved BNIP3 function in CRC cells lowers apoptosis, and may thus be involved in alternative cell death pathways, such as autophagic cell death. However, BNIP3 silencing in tumour cells does not impact on hypoxia-driven poorer prognosis. These results suggest that the biology of CRC cells can be modified by alterations in the tumour microenvironment under conditions of tumour hypoxia.

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Upregulation of BNIP3 by 5-aza-2′-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death

Cited by 62 publications

References 31 publications

Silencing of BNIP3 Results from Promoter Methylation by DNA Methyltransferase 1 Induced by the Mitogen-Activated Protein Kinase Pathway

Silencing of BNIP3 Results from Promoter Methylation by DNA Methyltransferase 1 Induced by the Mitogen-Activated Protein Kinase Pathway

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Poorer outcome in stromal HIF-2α- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis

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