Phosphatidylinositol 3-kinase/protein kinase B pathway stabilizes DNA methyltransferase I protein and maintains DNA methylation

Sun, Lidong; Zhao, Hongbo; Xu, Zhibin; Qinglan, Liu; Liang, Yulong; Wang, Liying; Cai, Xiumei; Zhang, Lineng; Hu, Libing; Wang, Guomin; Zha, Xiliang

doi:10.1016/j.cellsig.2007.06.014

Cited by 76 publications

(60 citation statements)

References 31 publications

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“…Deletion of p53 in human colon carcinoma cells and primary mouse astrocytes results in an increase in DNMT1 mRNA and protein, suggesting that p53 mediates the transcriptional repression of this gene (Peterson et al, 2003). Recently, it was shown that activation of the PI3K/Akt pathway increases DNMT1 protein levels (Sun et al, 2007). In the present study, we found that inhibition of p53 increases DNMT1 expression.…”

Section: Discussionsupporting

confidence: 69%

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

2011

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The mechanisms underlying the progression of noninvasive serous borderline ovarian tumors (SBOT) to low-grade invasive carcinomas are poorly understood. We recently showed that inhibition of p53 induces SBOT invasion by activating the PI3K/Akt pathway and transcriptionally repressing E-cadherin. In human cancers, aberrant DNA methylation is a common phenomenon, and it is thought to be involved in the progression from noninvasive to invasive ovarian carcinomas. In this study, we tested the hypothesis that inhibition of p53 downregulates E-cadherin by regulating the methylation of its promoter in SBOT cells. Here, we show that DNA methyltransferase-1 (DNMT1), but not DNMT3a or DNMT3b, was increased in SV40 LT-infected SBOT4 cells, SBOT4-LT and the low-grade invasive serous ovarian carcinomaderived cell line MPSC1. Treatment with 5-Aza-dC, a DNMT1 inhibitor, restored E-cadherin promoter methylation and expression, and inhibited cell invasion in both invasive SBOT4-LT and MPSC1 cells. Moreover, knockdown of endogenous p53 using siRNA in SBOT3.1 cells induced DNMT1 expression and led to an increase in E-cadherin promoter methylation. Additionally, activation of the PI3K/Akt pathway is required for p53 inhibitioninduced DNMT1 expression. The increase in DNMT1 was associated with the inhibition of p53-induced downregulation of E-cadherin and cell invasion. Our findings show an important role for p53 in the progression of SBOT to an invasive carcinoma, and suggest that downregulation of E-cadherin by DNMT1-mediated promoter methylation contributes to this process.

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Section: Discussionsupporting

confidence: 69%

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

2011

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“…The molecular link between CD28 activation and proteasome subunit downregulation remains to be determined, but it is likely to involve the PI3K/AKT pathway for several reasons: (1) binding of CD28 on MM cells triggers PI3K/AKT signaling 15 ; (2) PI3K/AKT signaling induces epigenetic silencing in tumors 32,33 ; and (3) treatment of tumor plasma cells with decitabine, a potent DNA methyltransferase inhibitor, restores proteasome subunit expression, as we have already reported. 13 Additional studies are also required to understand whether the reduced killing, by CD8…”

Section: Discussionmentioning

confidence: 90%

Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

Leone

Berardi

Frassanito

et al. 2015

Blood

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Key Points• Dendritic cells accumulate in the bone marrow of multiple myeloma patients.• Bone marrow dendritic cells play a dual, but opposing, role in multiple myeloma.Many researchers have speculated that the clinical progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by defects in dendritic cell (DC) function. However, evidence supporting this assumption is controversial, and no mechanism for the putative DC dysfunction has been demonstrated thus far. We studied DC subsets from the bone marrow of MM patients compared with those of MGUS patients and control subjects. We found that myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) accumulate in the bone marrow during the MGUS-to-MM progression. After engulfment of apoptotic tumor plasma cells via CD91, bone marrow mDCs and pDCs mature and are able to activate tumor-specific CD8 1 T cells. However, by interacting directly with CD28 on live (nonapoptotic) tumor plasma cells, bone marrow mDCs downregulate the expression of proteasome subunits in these cells, thus enabling their evasion from human leukocyte antigen (HLA) class I-restricted CD8 1 T-cell killing. These results suggest that DCs play a dual, but opposing, role in MM: for one, DCs activate CD8 1 T cells against tumor plasma cells and, for the other, DCs protect tumor plasma cells from CD8 1 T-cell killing. This information should be taken into account in designing immunotherapy approaches to enhance immune surveillance in MGUS and to break down immune tolerance in

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“…Because the AKT pathway was notably stimulated by NNK in all cell lines tested (Supplemental Figure 2), and a previous study reported that the AKT pathway stabilizes DNMT1 protein via decreased ubiquitination (24), it is possible that DNMT1 protein stability is induced by NNK through the AKT pathway. To test this hypothesis, we first measured DNMT1 protein levels during NNK treatment in the presence of the PI3K/AKT pathway inhibitor LY294002, which we found to potently block NNK-induced DNMT1 protein overexpression in A549 cells ( Figure 3C).…”

Section: Dnmt1 Overexpression Strongly Correlates With Smoking Statusmentioning

confidence: 99%

The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients

et al. 2010

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DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in many human diseases, including cancer. The tobacco-specific carcinogen NNK also induces DNA methylation. However, the role of DNMT1-mediated methylation in tobacco carcinogenesis remains unclear. Here we used human and mouse lung cancer samples and cell lines to determine a mechanism whereby NNK induced DNMT1 expression and activity. We determined that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated DNMT1 to recruit β-transducin repeat-containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation. NNK also induced βTrCP translocation to the cytoplasm via the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) shuttling protein, resulting in DNMT1 nuclear accumulation and hypermethylation of the promoters of tumor suppressor genes. Fluorescence immunohistochemistry (IHC) of lung adenomas from NNK-treated mice and tumors from lung cancer patients that were smokers were characterized by disruption of the DNMT1/βTrCP interaction and DNMT1 nuclear accumulation. Importantly, DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis. We believe that the NNK-induced DNMT1 accumulation and subsequent hypermethylation of the promoter of tumor suppressor genes may lead to tumorigenesis and poor prognosis and provide an important link between tobacco smoking and lung cancer. Furthermore, this mechanism may also be involved in other smoking-related human diseases.

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Phosphatidylinositol 3-kinase/protein kinase B pathway stabilizes DNA methyltransferase I protein and maintains DNA methylation

Cited by 76 publications

References 31 publications

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients

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