Deregulation of the CDX2-KLF4 axis in acute myeloid leukemia and colon cancer

Rouhi, A. Maureen; Fröhling, Stefan

doi:10.18632/oncotarget.896

Cited by 5 publications

(4 citation statements)

References 9 publications

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“…KLF4 expression has also been shown to be activated by AML1/RUNX1 (27), whereas the fusion protein AML1-ETO/RUNX1-MTG8 encoded by the t(8;21) translocation inhibits both KLF4 and CEBPA gene expression (17). KLF4 gene mutations have not been reported so far in patients with AML; however, we found an apparent loss of detectable KLF4 protein in our AML study cohort, again with lowest levels in the undifferentiated subtype M0 and in FLT3-ITD and NPM1-mutant AML, possibly due to overexpression of miR10A, Cdx2, or HDAC1 as suggested previously (8)(9)(10)(11).…”

Section: Discussionsupporting

confidence: 84%

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Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia

Seipel

Marques

Bozzini

et al. 2016

Clinical Cancer Research

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Purpose: In acute myeloid leukemia (AML), the transcription factors CEBPA and KLF4 as well as the universal tumor suppressor p53 are frequently deregulated. Here, we investigated the extent of dysregulation, the molecular interactions, and the mechanisms involved.Experimental Design: One hundred ten AML patient samples were analyzed for protein levels of CEBPA, KLF4, p53, and p53 modulators. Regulation of CEBPA gene expression by KLF4 and p53 or by chemical p53 activators was characterized in AML cell lines.Results: We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53-KLF4-CEBPA axis. In AML patient cells, we observed a prominent loss of p53 function and concomitant reduction of KLF4 and CEBPA protein levels. Assessment of cellular p53 modulator proteins indicated that p53 inactivation in leukemic cells correlated with elevated levels of the nuclear export protein XPO1/CRM1 and increase of the p53 inhibitors MDM2 and CUL9/PARC in the cytoplasm. Finally, restoring p53 function following treatment with cytotoxic chemotherapy compounds and p53 restoring nongenotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells.Conclusions: The p53-KLF4-CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments.

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Section: Discussionsupporting

confidence: 84%

“…Alike CEBPA, KLF4 can arrest cell proliferation via induction of the CDKN1A gene, and it represents a potent p53 mediator, thus acting as a tumor suppressor (7). KLF4 expression is downregulated in NPM1-mutant AML by miR10a (8), and it can be repressed by CDX2 and HDAC1 (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia

Seipel

Marques

Bozzini

et al. 2016

Clinical Cancer Research

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“…Recently, evidence has suggested that Klf4 may serve as a tumor suppressor in leukemia. 23 , 24 Previous studies have demonstrated that Klf4 is repressed by CDX2 in AML and colon cancer, 25 and downregulation of Klf4 by Jak2 allows for increased proliferation of progenitor cells. 26 However, the exact role of Klf4 and HDACs in leukemia, particularly in AML, is unclear.…”

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confidence: 99%

HDAC1 and Klf4 interplay critically regulates human myeloid leukemia cell proliferation

Huang¹,

Chen

et al. 2014

Cell Death Dis

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Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain unclear. General histone deacetylase (HDAC) inhibitors have been used in blood cancers including AML, but the lack of gene specificity greatly limits their anti-cancer effects and clinical applications. Here, we found that HDAC1 expression was negatively correlated with that of Krüppel-like factor 4 (Klf4) and that AML patients with lower HDAC1 level had better prognosis. Further, knockdown of HDAC1 in leukemia cells K562, HL-60, and U937 significantly increased Klf4 expression and inhibited cell cycle progression and cell proliferation, similar results were found for HDAC inhibitors (VPA and mocetinostat). Moreover, overexpression or knockdown of Klf4 could markedly block the effects of HDAC1 overexpression or knockdown on leukemia cells in vitro and in vivo, respectively. Mechanistic analyses demonstrated that HDAC1 and Klf4 competitively bound to the promoter region of Klf4 and oppositely regulated Klf4 expression in myeloid leukemia. We identified HDAC1 as a potential specific target for repressing cell proliferation and inducing cell cycle arrest through interplay and modulation of Klf4 expression, suggests that HDAC1 and Klf4 are potential new molecular markers and targets for clinical diagnosis, prognosis, and treatment of myeloid leukemia.

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“…CDX2 is a nuclear homeobox transcription factor in the caudal-associated family of CDX homeobox genes ( 33 ). CDX2 functions in the control of normal embryonic development, cell proliferation, differentiation, adhesion and apoptosis ( 34 – 38 ). CDX2 is upregulated in numerous types of human gastrointestinal cancer and mutations in CDX2 in gastric epithelial cells are associated with tumorigenesis ( 39 – 42 ).…”

Section: Discussionmentioning

confidence: 99%

SLC6A1‑miR133a‑CDX2 loop regulates SK‑OV‑3 ovarian cancer cell proliferation, migration and invasion

Zhao

Zhou

et al. 2018

Oncol Lett

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The present study assessed the expression of solute carrier 6 member 1 (SLC6A1) in ovarian cancer (OC) tissues and evaluated the effect of silencing SLC6A1 or caudal type homeobox 2 (CDX2) on the proliferation, migration, and invasion of SK-OV-3 OC cells. The levels of caudal type homeobox 2 (CDX2) and SLC6A1 mRNA were also examined in OC SK-OV-3, OVCAR3 and A2780 cell lines. The mRNA levels of CDX2 and SLC6A1 in SK-OV-3 OC cells were assessed following transection with microRNA (miR) 133a mimics; the mRNA and protein levels of SLC6A1 were determined following the silencing of CDX2, and the mRNA expression of CDX2 was gauged following the silencing of SLC6A1. A luciferase reporter assay was performed to assess the effect of miR133a on the CDX2 and SLC6A1 3′-untranslated regions (3′UTRs). The proliferation, migration and invasion rate of SK-OV-3 cells were then examined following the silencing of CDX2 or SLC6A1. The expression of SLC6A1 was increased in OC compared with adjacent tissue. The expression of CDX2 and SLC6A1 in SK-OV-3 and OVCAR3 cells was increased compared with A2780 cells (P<0.05). The level of CDX2 and SLC6A1 mRNA in SK-OV-3 cells decreased when the cells were transected with the miR133a mimics, compared with a negative control (P<0.05). Transfection with the miR133a mimics significantly reduced the luciferase activity of reporter plasmids with the SLC6A1 or CDX2 3′UTRs (P<0.05). The mRNA level of CDX2 was decreased subsequent to the silencing of SLC6A1; the mRNA and protein level of SLC6A1 were decreased when CDX2 was silenced (P<0.05). The proliferation, migration, and invasion of SK-OV-3 cells were significantly reduced following the silencing of CDX2 or SLC6A1 (P<0.05). CDX2 may therefore be inferred to promote the proliferation, migration and invasion in SK-OV-3 OC cells, acting as a competing endogenous RNA.

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Deregulation of the CDX2-KLF4 axis in acute myeloid leukemia and colon cancer

Cited by 5 publications

References 9 publications

Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia

Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia

HDAC1 and Klf4 interplay critically regulates human myeloid leukemia cell proliferation

SLC6A1‑miR133a‑CDX2 loop regulates SK‑OV‑3 ovarian cancer cell proliferation, migration and invasion

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