Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma

Nagel, Stefan; Schneider, Björn; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans; MacLeod, Roderick A.F.

doi:10.1016/j.leukres.2011.10.019

Cited by 42 publications

(67 citation statements)

References 61 publications

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“…2E ). Of note, we recently showed reduced expression of ZHX2 in HL cell line L-1236 and an activating input of homeobox gene MSX1 [27]. Accordingly, siRNA-mediated knockdown of MSX1 in SU-DHL-5 reduced transcription of ZHX2 but not of HEY1 ( Fig.…”

Section: Resultsmentioning

confidence: 72%

Ectopic Expression of Homeobox Gene NKX2-1 in Diffuse Large B-Cell Lymphoma Is Mediated by Aberrant Chromatin Modifications

et al. 2013

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Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2-1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies.

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Section: Resultsmentioning

confidence: 72%

Ectopic Expression of Homeobox Gene NKX2-1 in Diffuse Large B-Cell Lymphoma Is Mediated by Aberrant Chromatin Modifications

et al. 2013

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“…13,14,42,45 However, ZHX2 has been implicated in cancer in other tissues. 46 In contrast, ZHX2 appears to be higher expressed in renal cell carcinoma. 25 This chromosomal rearrangement reduces ZHX2 expression, possibly by the loss of binding sites for the transcriptional activators MSX1 and XBP1 upstream of the ZHX2 gene.…”

Section: Discussionmentioning

confidence: 91%

HBV suppresses ZHX2 expression to promote proliferation of HCC through miR‐155 activation

Song

Tan

et al. 2018

Intl Journal of Cancer

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Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a complex process that includes both oncogene activation and tumor suppressor inhibition. The HBV X (HBx) protein has an important and complex role in processes leading to HCC. We previously identified the mammalian Zinc fingers and homeoboxes 2 (ZHX2) gene as an HCC-associated tumor suppressor gene. In the present study, we investigated whether the oncogenic properties of HBV and, more specifically, HBx, involved ZHX2 silencing. Our data indicates that ZHX2 expression is significantly decreased in tumor tissues from HBV-positive HCC patients and livers from HBV transgenic mice. In vitro and in vivo studies confirmed that HBV-encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. Further analyses identified miR-155, a well-known oncomiR in various cancers, as an important link between HBx and ZHX2 inhibition. Increased miR-155 levels were found in HBV-positive tumors, livers of HBV transgenic mice and HBx-overexpressing hepatoma cell lines. MiR-155 overexpression reduced ZHX2 levels via miR-155 seed sites in the ZHX2 3'UTR, whereas blocking miR-155 levels led to increased ZHX2 levels. Taken together, our data indicate that HCC-promoting properties of HBV may include ZHX2 silencing via a miR-155 dependent pathway and suggests a novel therapy for HBV-related HCC.

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“…C). Recently, we demonstrated deregulated expression of homeobox gene MSX1 in HL cells and showed that FOXC1 regulates MSX1 in mantle cell lymphoma cells (Nagel et al, , in press). Here, MSX1 transcript levels increased after knockdown of FOXC1, indicating an inhibitory impact (Fig.…”

Section: Resultsmentioning

confidence: 98%

Deregulated FOX genes in Hodgkin lymphoma

Nagel

Meyer

Kaufmann

et al. 2014

Genes Chromosomes & Cancer

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FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFβ- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets.

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Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma

Cited by 42 publications

References 61 publications

Ectopic Expression of Homeobox Gene NKX2-1 in Diffuse Large B-Cell Lymphoma Is Mediated by Aberrant Chromatin Modifications

Ectopic Expression of Homeobox Gene NKX2-1 in Diffuse Large B-Cell Lymphoma Is Mediated by Aberrant Chromatin Modifications

HBV suppresses ZHX2 expression to promote proliferation of HCC through miR‐155 activation

Deregulated FOX genes in Hodgkin lymphoma

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