Regulation of the Potential Marker for Intestinal Cells, Bmi1, by β-Catenin and the Zinc Finger Protein KLF4

Yu, Ting; Chen, Xi; Zhang, Wen; Colon, Deannon; Shi, Jiandang; Napier, Dana; Rychahou, Piotr G.; Lu, Wange; Lee, Eun Y.; Weiss, Heidi L.; Evers, B. Mark; Liu, Chunming

doi:10.1074/jbc.m111.316349

Cited by 86 publications

(77 citation statements)

References 44 publications

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“…9). Recently, it was reported that in colon cancer cells the WNT pathway can regulate expression of BMI1 (40). We confirmed that, similar to colon cancer cells, overexpression of Wnt1 and knockdown of DKK1 lead to BMI1 up-regulation in human mammary epithelial cells.…”

Section: Discussionsupporting

confidence: 73%

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A Positive Feedback Loop Regulates the Expression of Polycomb Group Protein BMI1 via WNT Signaling Pathway

Cho

Dimri

2013

Journal of Biological Chemistry

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Background: PcG protein BMI1 is transcriptionally regulated by Myc and is up-regulated in cancer cells. Results:The WNT pathway plays an important role in Myc regulation of BMI1. Conclusion: BMI1 up-regulates the WNT pathway, which in turn regulates expression of BMI1 via c-Myc. Significance: The study provides insights into the regulation of BMI1 and suggests that BMI1 expression may be targeted by WNT inhibitors in cancer cells.

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Section: Discussionsupporting

confidence: 73%

“…ChIP qPCR primer sets 40 g was run on SDS-PAGE, transferred to a PVDF membrane, and probed with respective antibodies. Soft Agar and Mammosphere Formation Assays-The soft agar assay to measure the anchorage-independent growth was performed as described previously (5,29).…”

Section: Real Time Rt-pcr Primer Setsmentioning

confidence: 99%

A Positive Feedback Loop Regulates the Expression of Polycomb Group Protein BMI1 via WNT Signaling Pathway

Cho

Dimri

2013

Journal of Biological Chemistry

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“…Hypoxia-induced Twist1 directly activated BMI1 transcription, and cooperatively acted with Bmi1 to induce an epithelial-mesenchymal transition and stemness properties in head and neck squamous cell carcinoma [15,16]. Other transcription factors, such as SALL4 and c-Myb have also been identified as activators of BMI1 transcription in both hematopoietic and leukemic cells, while nuclear factorjB (NF-jB) and the sonic hedgehog-activated Gli1 are potent transcription factors in Hodgkin lymphoma and medulloblastoma cells, respectively [17][18][19][20][21]. Although there are many studies addressing Bmi1 regulation, a detailed promoter analysis has yet to be conducted, and the underlying mechanisms remain elusive; therefore, these issues deserve to be investigated in more detail.…”

Section: Introductionmentioning

confidence: 99%

Sp1 and c‐Myc regulate transcription of BMI1 in nasopharyngeal carcinoma

et al. 2013

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B-lymphoma mouse Moloney leukemia virus insertion region 1 (Bmi1), a member of the polycomb group, has elevated expression and is involved in the pathogenesis of various aggressive cancers, including nasopharyngeal carcinoma (NPC). To date, the mechanisms underlying the high expression of Bmi1 in NPC remain obscure. To gain new insights into the transcriptional regulation of BMI1, we cloned and characterized the promoter region of BMI1. Luciferase reporter assays demonstrated that the region from À783 to +375 showed significant promoter activity. With the use of a series of 5′-deletion and 3′-deletion promoter constructs in luciferase reporter assays, the +167/+232 and À536/À134 regions were found to be sufficient for full promoter activity. Transcriptional activity of the BMI1 promoter was dependent on the Sp1 binding site cluster (+181/ +214) as well as the E-box elements (À181), and was abolished after mutation of the two cis-elements. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays demonstrated that Sp1 bound to the region from +181 to +214 within the BMI1 promoter. In addition, gain-of-function and loss-of-function analyses revealed that Sp1 augmented Bmi1 expression. Further investigations using immunohistochemistry and quantitative RT-PCR disclosed a significant positive correlation between the expression of Sp1 and Bmi1 in normal nasopharyngeal epithelial cells, NPC cells, and NPC tissue specimens. In addition, Myc, the known transcription factor for BMI1 in neuroblastomas, also activated the transcription of BMI1 through binding to the E-box element (À181) within its promoter, and showed a positive correlation with the mRNA level of BMI1 in NPC. In conclusion, these findings provide valuable mechanistic insights into the role of Sp1 and c-Myc in BMI1 transcription in NPC, and suggest that targeting of Sp1 or c-Myc may be a potential therapeutic strategy for NPC.

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“…43 Our previous finding suggests that KLF4 inhibits Bmi1 expression in colorectal tumorigenesis. 44 Using the mouse model from our current study, IHC staining of Bmi1 in the lung tissue showed that Bmi1 is overexpressed in tumor tissue in the K-ras LSL-G12D/+ ;Klf4 fl/fl mouse (Supplementary Figure 8). Both Bmi1 and AT2 cell markers were increased in the tumors, suggesting that KLF4 deletion induced tumorinitiating cells during lung tumorigenesis.…”

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confidence: 99%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifeninduced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras LSL-G12D/+ ;Klf4 fl/fl mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

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Regulation of the Potential Marker for Intestinal Cells, Bmi1, by β-Catenin and the Zinc Finger Protein KLF4

Cited by 86 publications

References 44 publications

A Positive Feedback Loop Regulates the Expression of Polycomb Group Protein BMI1 via WNT Signaling Pathway

A Positive Feedback Loop Regulates the Expression of Polycomb Group Protein BMI1 via WNT Signaling Pathway

Sp1 and c‐Myc regulate transcription of BMI1 in nasopharyngeal carcinoma

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

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