Opposing Functions of BRD4 Isoforms in Breast Cancer

Wu, Shwu Yuan; Lee, Chien Fei; Lai, Hsien Tsung; Yu, Cheng Tai; Lee, Ji Eun; Zuo, Hao; Tsai, Sophia Y.; Tsai, Ming Jer; Ge, Kai; Wan, Yihong; Chiang, Cheng Ming

doi:10.1016/j.molcel.2020.04.034

Cited by 112 publications

(131 citation statements)

References 98 publications

(69 reference statements)

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“…These results strongly indicate that sex differences in disease biology translate into sex differences in therapeutic responses. The sex-specific response to the inhibition of Brd4 in our GBM model could help explain previously published data in breast and prostate cancer, wherein ectopic expression of Brd4 in breast cancer cells decreased invasiveness and tumor growth, while Brd4 inhibition decreased viability of prostate cancer cells (40,(70)(71)(72). These studies also revealed that in women with estrogen receptor positive breast cancer (70) or endometrial cancer (71), low Brd4 expression correlated with worse survival.…”

Section: Discussionsupporting

confidence: 81%

Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma

Kfoury

Prager

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma (GBM), we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited sex-specific responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET (bromodomain and extraterminal) inhibitors than are female cells. Thus, Brd4 activity is revealed to drive sex differences in stem cell and tumorigenic phenotypes, which can be abrogated by sex-specific responses to BET inhibition. This has important implications for the clinical evaluation and use of BET inhibitors.

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Section: Discussionsupporting

confidence: 81%

Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma

Kfoury

Prager

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…7A–D ). Previously, it has been documented that BRD4 is capable of promoting cancer cell growth and invasion 28 , 29 , 39 . Here, we show that SNHG18 can enhance the expression of BRD4, and miR-211-5p prevents SNHG18-mediated upregulation of BRD4.…”

Section: Discussionmentioning

confidence: 99%

MKL1-induced lncRNA SNHG18 drives the growth and metastasis of non-small cell lung cancer via the miR-211-5p/BRD4 axis

Fan

Yuan

et al. 2021

Cell Death Dis

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Megakaryocytic leukemia 1 (MKL1) is a key transcription factor involved in non-small cell lung cancer (NSCLC) growth and metastasis. Yet, its downstream target genes, especially long non-coding RNA (lncRNA) targets, are poorly investigated. In this study, we employed lncRNA array technology to identify differentially expressed lncRNAs in NSCLC cells with or without overexpression of MKL1. Candidate lncRNAs were further explored for their clinical significance and function in NSCLC. The results showed that MKL1 promoted the expression of lncRNA SNHG18 in NSCLC cells. SNHG18 upregulation in NSCLC specimens correlated with lymph node metastasis and reduced overall survival of NSCLC patients. SNHG18 expression served as an independent prognostic factor for NSCLC. Knockdown of SNHG18 blocked MKL1-induced growth and invasion of NSCLC cells in vitro. Animal studies validated the requirement for SNHG18 in NSCLC growth and metastasis. Moreover, overexpression of SNHG18 promoted NSCLC cell proliferation and invasion. Mechanically, SNHG18 exerted its prometastatic effects on NSCLC cells through repression of miR-211-5p and induction of BRD4. Clinical evidence indicated that SNHG18 expression was negatively correlated with miR-211-5p expression in NSCLC tissues. Altogether, SNHG18 acts as a lncRNA mediator of MKL1 in NSCLC. SNHG18 facilitates NSCLC growth and metastasis by modulating the miR-211-5p/BRD4 axis. Therefore, SNHG18 may be a potential therapeutic target for the treatment of NSCLC.

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“…The Long and the Short of BRD4: Two Tales in Breast Cancer Sicong Zhang 1, * and Robert G. Roeder 1, * In this issue of Molecular Cell, Wu et al (2020) describe studies that establish oncogenic versus tumorsuppressive functions of two BRD4 isoforms in the regulation of gene expression and breast cancer development.…”

mentioning

confidence: 99%

“…However, the question of how this result relates to the native BRD4 isoform-specific mechanisms and the biological processes they regulate has remained unaddressed. In the current issue of Molecular Cell, Wu et al report significant progress in understanding the differential roles of BRD4 isoforms and how they might impact breast cancer (BCa) therapy (Wu et al, 2020).…”

mentioning

confidence: 99%