KLF5 promotes breast cancer proliferation, migration and invasion in part by upregulating the transcription of TNFAIP2

Jia, Lin; Zhou, Zhongmei; Liang, Hongjun; Wu, Jianhua; Shi, Peng; Li, F; Wang, Z; Wang, C; Chen, W; Zhang, H; Wang, Y; Liu, R; Feng, Jing; Chen, C

doi:10.1038/onc.2015.263

Cited by 128 publications

(155 citation statements)

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“…Because it has been suggested that several cancer-promoting genes, such as Akt [38], c-Myc [32], KLF5 [33], and DRD2 [34] are involved in cell survival or proliferation in BCa cells, we sought to compare the status of these genes in human TNBC tumors versus non-TNBC tumors. Thus, we analyzed the gene amplification and mRNA copy number gain (amplification/gain) data available from The Cancer Genome Atlas (TCGA) datasets using cBioPortal [39, 40].…”

Section: Resultsmentioning

confidence: 99%

“…Activation of FOXO3 tumor suppressor by TFP or BPD is a significant distinction from traditional antipsychotic inhibitors and the resultant downregulation of oncogenic survival factors, c-Myc [32] and Kruppel-like factor 5 (KLF5) [33], in TNBC is an interesting anticancer mechanism. Unexpectedly, we uncover that both TFP and BPD display suppression of the expression of the dopamine receptor D2 (DRD2), which has been suggested as a key receptor for selective-targeting cancer stem cells (CSC) [34], in a FOXO3-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

Park

Chung

et al. 2016

Oncotarget

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Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer. Lacking effective therapeutic options hinders treatment of TNBC. Here, we show that bepridil (BPD) and trifluoperazine (TFP), which are FDA-approved drugs for treatment of schizophrenia and angina respectively, inhibit Akt-pS473 phosphorylation and promote FOXO3 nuclear localization and activation in TNBC cells. BPD and TFP inhibit survival and proliferation in TNBC cells and suppress the growth of TNBC tumors, whereas silencing FOXO3 reduces the BPD- and TFP-mediated suppression of survival in TNBC cells. While BPD and TFP decrease the expression of oncogenic c-Myc, KLF5, and dopamine receptor DRD2 in TNBC cells, silencing FOXO3 diminishes BPD- and TFP-mediated repression of the expression of these proteins in TNBC cells. Since c-Myc, KLF5, and DRD2 have been suggested to increase cancer stem cell-like populations in various tumors, reducing these proteins in response to BPD and TFP suggests a novel FOXO3-dependent mechanism underlying BPD- and TFP-induced apoptosis in TNBC cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

Park

Chung

et al. 2016

Oncotarget

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“…6D). COMMD7 (You et al ., 2017), ITGA1 (Boudjadi et al ., 2013; Gulubova, 2004; Schadendorf et al ., 1996), RAB3D (Luo et al ., 2016; Yang et al ., 2003), and TNFAIP2 (Chen et al ., 2011; Jia et al ., 2016) have all been shown to be upregulated in various cancers including PDAC. While we cannot assume these changes will be universal in all PDAC samples, this consistency suggests that some of these genes could make promising targets or biomarkers for APE1‐based therapy or combination therapies that potentially will be useful across multiple PDAC tumor subtypes and in other tumor types.…”

Section: Discussionmentioning

confidence: 99%

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

et al. 2017

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Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer‐related pathways. Because APE1 is essential for cell viability, generation of APE1‐knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single‐cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial‐related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT‐PCR. Testing additional patient‐derived pancreatic cancer cells reveals particular genes (ITGA1,TNFAIP2,COMMD7,RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox‐specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis‐driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.

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“…For Re-ChIP, the primary ChIP material was released from the agaroses and subjected to second round of immunoprecipitation using corresponding Abs. For chromatin immunodepletion (ChID), ChIP material isolated from the agaroses was immunoprecipitated again with an anti-Ac-K Ab, and GDF15 promoter fragment in the supernatant immunodepleted with anti-Ac-K was detected [15, 27]. The primers for GDF15 promoter fragments were as follows: primer for −234 to −76 nt, forward: 5′-GGCTGGAATGGTGTCCT-3′, reverse: 5′-CCCCTGCCTGCAGAGTA-3′; primer for −103 to +58, forward: 5′-TCAAACAATCCACCCACCT-3′, reverse: 5′-TTTCCAGTCTAAGCAGGGTG-3′.…”

Section: Methodsmentioning

confidence: 99%

“…Reportedly, kruppel-like factor 5 (KLF5), as a transcription factor, can boost breast cancer cell proliferation [15], and activate sox4 or HIF-1α transcription via binding to GC-rich DNA sequences, resulting in lung cancer proliferation [16]. Moreover, as a transcriptional co-activator, general control non-depressible (GCN5) potentiates NSCLC growth by increasing E2F1 and cyclin D1 expression [17] and accelerates glioma development as well [18].…”

Section: Introductionmentioning

confidence: 99%

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Zhao

Qiu

et al. 2018

Oncogene

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

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KLF5 promotes breast cancer proliferation, migration and invasion in part by upregulating the transcription of TNFAIP2

Cited by 128 publications

References 50 publications

Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

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