Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis

Liang, Yajun; Wu, Hui; Rong, Lei; Chong, Robert; Wei, Yong; Lü, Xin; Tagkopoulos, Ilias; Kung, Sun Yuan; Yang, Qifeng; Hu, Guohong; Kang, Yibin

doi:10.1074/jbc.m112.392332

Cited by 124 publications

(121 citation statements)

References 40 publications

(70 reference statements)

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“…Metastasis is thought to result from changes in the expression of specific genes (e.g. upregulation) that lead to activation of multiple downstream genes mediating the metastatic process ( Figure 1 ) 56. Such metastasis-driving genes could serve as effective therapeutic targets for management of metastatic prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

2014

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Metastatic prostate cancer is currently incurable. Metastasis is thought to result from changes in the expression of specific metastasis-driving genes in nonmetastatic prostate cancer tissue, leading to a cascade of activated downstream genes that set the metastatic process in motion. Such genes could potentially serve as effective therapeutic targets for improved management of the disease. They could be identified by comparative analysis of gene expression profiles of patient-derived metastatic and nonmetastatic prostate cancer tissues to pinpoint genes showing altered expression, followed by determining whether silencing of such genes can lead to inhibition of metastatic properties. Various hurdles encountered in this approach are discussed, including (i) the need for clinically relevant, nonmetastatic and metastatic prostate cancer tissues such as xenografts of patients’ prostate cancers developed via subrenal capsule grafting technology and (ii) limitations in the currently available methodology for identification of master regulatory genes.

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Section: Introductionmentioning

confidence: 99%

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

2014

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“…Recently, growing evidence revealed BACH1 in the case of cancer progression. Liang et al 14. revealed that ectopic expression of BACH1 is involved in enhancement malignancy of breast cancer cells while knockdown considerably suppresses these processes.…”

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confidence: 99%

BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53

Nie

Jin

et al. 2016

Sci Rep

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The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance.

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“…According to the study on breast cancer metastasis and the genes involved, by Liang et al, 19 it was reported that bach1 had a role in the expansion of breast cancer metastasis to bones. Bach1 inhibition in a mouse model of metastasis reduced metastasis dramatically, and uncontrolled overexpression of bach1 leads to increased malignant breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Silencing of bach1 gene by small interfering RNA–mediation regulates invasive and expression level of miR-203, miR-145, matrix metalloproteinase-9, and CXCR4 receptor in MDA-MB-468 breast cancer cells

2017

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Background: Recently experimental validation of the networks revealed bach1, a basic leucine zipper transcription factor, as the common regulator of several functional invasive genes. The expression of bach1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. The aim of this study was to investigate the effect of specific bach1 small interfering RNAs, on the invasive and expression level of miR-203, miR-145, matrix metalloproteinase-9, and CXCR4 receptor which play a role in cancer metastasis, in MDA-MB-468 cell lines. Methods: Small interfering RNA transfection was performed with transfection regent. The survival effects of small interfering RNA were determined using trypan blue assay cells. The expression level of messenger RNA and matrix metalloproteinase-9 to assess cell invasion and the expression level of miR-203, miR-145, and CXCR4 receptor were measured by quantitative real-time polymerase chain reaction analysis on the MDA-MB-468 cell lines. Results: Transfection with small interfering RNA significantly suppressed the expression of bach1 gene in dose-dependent manner after 48 h (p < 0.0001). A significant reduction in cell invasion and CXCR4 receptor, matrix metalloproteinase-9 expression were observed (p < 0.0001). It was also a dramatic increase in the expression level of miR-203 and miR-145 (p < 0.0001). Conclusions: Our results suggest that the bach1-specific small interfering RNA effectively decrease CXCR4 receptor, matrix metalloproteinase-9 expression and breast adenocarcinoma cells invasive, also increased the expression of tumor-suppressive microRNA-203 and miR-145. Thus, these microRNAs may play a role in invasive/metastasis of carcinogenic breast cancer cells. Therefore, bach1 knockdown can be considered as a potent adjuvant in breast cancer therapy.

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Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis

Cited by 124 publications

References 40 publications

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53

Silencing of bach1 gene by small interfering RNA–mediation regulates invasive and expression level of miR-203, miR-145, matrix metalloproteinase-9, and CXCR4 receptor in MDA-MB-468 breast cancer cells

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