Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBPα and GATA-1 in myeloid leukemia with MLL-AF9

Lee, Jae Woong; Kim, Hyeng-Soo; Hwang, Junmo; Kim, Young Hun; Lim, Ga Young; Sohn, Wern‐Joo; Yoon, Suk-Ran; Park, Tae Sung; Oh, Seung Hwan; Park, Kwon Moo; Choi, Sang Un; Ryoo, Zae Young; Lee, Sanggyu

doi:10.1016/j.bbrc.2012.08.048

Cited by 17 publications

(12 citation statements)

References 21 publications

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“…28, 29, 30 DACH1 is expressed in normal epithelium but its expression is significantly reduced in breast, prostate and endometrial cancer. 31, 32, 33 DACH1 regulates its target genes, in part by interacting with transcription factors, including HOXA9, p53, SMADs, SIX and others, 28, 34, 35, 36, 37 and also by binding to the DNA via AP-1, NF-κB and Forkhead binding sites. 38, 39 The role of DACH1 in the inhibition of oncogene-induced cellular migration and metastasis is well established in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

DACH1 inhibits SNAI1-mediated epithelial–mesenchymal transition and represses breast carcinoma metastasis

Zhao

Wang

et al. 2015

Oncogenesis

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Epithelial–mesenchymal transition (EMT) has a major role in cancer progression and metastasis. However, the specific mechanism of transcriptional repression involved in this process remains largely unknown. Dachshund homologue 1 (DACH1) expression is lost in invasive breast cancer with poor prognosis, and the role of DACH1 in regulating breast cancer metastasis is poorly understood. In this study, significant correlation between the expression of DACH1 and the morphology of breast cancer cells was observed. Subsequent investigation into the relationship between DACH1 and EMT showed that overexpression of DACH1 in ZR-75-30 cells induced a shift towards epithelial morphology and cell–cell adhesion, as well as increased the expression of the epithelial marker E-cadherin and suppressed cell migration and invasion. In contrast, silencing DACH1 in MCF-7 and T47D cells disrupted the epithelial morphology and cell–cell contact, reduced the expression of E-cadherin, and induced cell migration and invasion. DACH1 also specifically interacted with SNAI1, but not SNAI2, to form a complex, which could bind to the E-box on the E-cadherin promoter in an SNAI1-dependent manner. DACH1 inhibited the transcriptional activity of SNAI1, leading to the activation of E-cadherin in breast cancer cells. Furthermore, the level of DACH1 also correlated with the extent of metastasis in a mouse model. DACH1 overexpression significantly decreased the metastasis and growth of 4T1/Luc cells in BALB/c mice. Analysis of tissue samples taken from human breast cancers showed a significant correlation between the expression of DACH1 and E-cadherin in SNAI1-positive breast cancer. Collectively, our data identified a new mechanistic pathway for the regulation of EMT and metastasis of breast cancer cells, one that is based on the regulation of E-cadherin expression by direct DACH1–SNAI1 interaction.

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Section: Introductionmentioning

confidence: 99%

DACH1 inhibits SNAI1-mediated epithelial–mesenchymal transition and represses breast carcinoma metastasis

Zhao

Wang

et al. 2015

Oncogenesis

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“… 18 , 19 , 20 It has been shown that aberrant chromosomal rearrangements of KMT2A generated the MLL-AF9 fusion protein that initiated murine acute myeloid leukemia. 21 Other reports have shown that MLL fusion oncoprotein drive the expression of homeobox genes such as HOXA cluster genes and myeloid ecotropic viral integration site 1, which are known to induce leukemic transformation of hematopoietic progenitors and predict poor diagnosis for the disease. 22 Furthermore, the expression of KMT2A is usually essential for the senescence-associated secretory phenotype, 23 and KMT2A has been found to interact with the NF- κ B pathway to regulate brain cancer growth.…”

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confidence: 99%

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

et al. 2017

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Melanoma is an aggressive cutaneous malignancy, illuminating the exact mechanisms and finding novel therapeutic targets are urgently needed. In this study, we identified KMT2A as a potential target, which promoted the growth of human melanoma cells. KMT2A knockdown significantly inhibited cell viability and cell migration and induced apoptosis, whereas KMT2A overexpression effectively promoted cell proliferation in various melanoma cell lines. Further study showed that KMT2A regulated melanoma cell growth by targeting the hTERT-dependent signal pathway. Knockdown of KMT2A markedly inhibited the promoter activity and expression of hTERT, and hTERT overexpression rescued the viability inhibition caused by KMT2A knockdown. Moreover, KMT2A knockdown suppressed tumorsphere formation and the expression of cancer stem cell markers, which was also reversed by hTERT overexpression. In addition, the results from a xenograft mouse model confirmed that KMT2A promoted melanoma growth via hTERT signaling. Finally, analyses of clinical samples demonstrated that the expression of KMT2A and hTERT were positively correlated in melanoma tumor tissues, and KMT2A high expression predicted poor prognosis in melanoma patients. Collectively, our results indicate that KMT2A promotes melanoma growth by activating the hTERT signaling, suggesting that the KMT2A/hTERT signaling pathway may be a potential therapeutic target for melanoma.

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“…5B-D). Notably, DACH1 has been suggested to play a role as a coactivator in myeloid cells (44,45) and there is growing evidence that nuclear pore components, such as POM121, additionally localize to the nucleoplasm and activate transcription (46,47). However, none of the PAX5 fusion proteins exhibited Cd79a transactivation capability in murine 558LmM cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development

Fortschegger

Anderl

Denk

et al. 2014

Molecular Cancer Research

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PAX5, a transcription factor pivotal for B-cell commitment and maintenance, is one of the most frequent targets of somatic mutations in B-cell precursor acute lymphoblastic leukemia. A number of PAX5 rearrangements result in the expression of in-frame fusion genes encoding chimeric proteins, which at the N-terminus consistently retain the PAX5 DNA-binding paired domain fused to the C-terminal domains of a markedly heterogeneous group of fusion partners. PAX5 fusion proteins are thought to function as aberrant transcription factors, which antagonize wild-type PAX5 activity. To gain mechanistic insight into the role of PAX5 fusion proteins in leukemogenesis, the biochemical and functional properties of uncharacterized fusions: PAX5-DACH1, PAX5-DACH2, PAX5-ETV6, PAX5-HIPK1, and PAX5-POM121 were ascertained. Independent of the subcellular distribution of the wild-type partner proteins, ectopic expression of all PAX5 fusion proteins showed a predominant nuclear localization, and by chromatin immunoprecipitation all of the chimeric proteins exhibited binding to endogenous PAX5 target sequences. Furthermore, consistent with the presence of potential oligomerization motifs provided by the partner proteins, the self-interaction capability of several fusion proteins was confirmed. Remarkably, a subset of the PAX5 fusion proteins conferred CD79A promoter activity; however, in contrast with wild-type PAX5, the fusion proteins were unable to induce Cd79a transcription in a murine plasmacytoma cell line. These data show that leukemia-associated PAX5 fusion proteins share some dominating characteristics such as nuclear localization and DNA binding but also show distinctive features.Implications: This comparative study of multiple PAX5 fusion proteins demonstrates both common and unique properties, which likely dictate their function and impact on leukemia development.

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Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBPα and GATA-1 in myeloid leukemia with MLL-AF9

Cited by 17 publications

References 21 publications

DACH1 inhibits SNAI1-mediated epithelial–mesenchymal transition and represses breast carcinoma metastasis

DACH1 inhibits SNAI1-mediated epithelial–mesenchymal transition and represses breast carcinoma metastasis

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development

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