KLF9 suppresses cell growth and induces apoptosis via the AR pathway in androgen-dependent prostate cancer cells

Shen, Pengliang; Cao, Xiaoming; Sun, Lili; Qian, Yu; Wu, Bo; Wang, Xin; Shi, Guowei; Wang, Dongwen

doi:10.1016/j.bbrep.2021.101151

Cited by 8 publications

(12 citation statements)

References 27 publications

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“…It is likewise directly induced by GC signaling in different cellular contexts [ 14 , 18 , 52 ], and antagonizes E2-mediated transcriptional activity in endometrial epithelial cells [ 19 ]. Underscoring the emerging role KFL9 in hormone-responsive neoplasms, knockout of Klf9 in mice increased overall endometrial carcinoma burden [ 65 ], while its ectopic expression promoted apoptosis in androgen-dependent prostate cancer cells [ 66 ] and restricted BCa metastatic spread [ 20 ]. Despite mounting evidence implicating KLF9 as a tumor suppressor, its role in the emerging link between hormone signaling, circadian disruption, and BCa development is yet to be explored.…”

Section: Discussionmentioning

confidence: 99%

Krüppel-like factor 9 (KLF9) links hormone dysregulation and circadian disruption to breast cancer pathogenesis

Ybañez

Bagamasbad

2023

Cancer Cell Int

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Background Circadian disruption is an emerging driver of breast cancer (BCa), with epidemiological studies linking shift work and chronic jet lag to increased BCa risk. Indeed, several clock genes participate in the gating of mitotic entry, regulation of DNA damage response, and epithelial-to-mesenchymal transition, thus impacting BCa etiology. Dysregulated estrogen (17β-estradiol, E2) and glucocorticoid (GC) signaling prevalent in BCa may further contribute to clock desynchrony by directly regulating the expression and cycling dynamics of genes comprising the local breast oscillator. In this study, we investigated the tumor suppressor gene, Krüppel-like factor 9 (KLF9), as an important point of crosstalk between hormone signaling and the circadian molecular network, and further examine its functional role in BCa. Methods Through meta-analysis of publicly available RNA- and ChIP-sequencing datasets from BCa tumor samples and cell lines, and gene expression analysis by RT-qPCR and enhancer- reporter assays, we elucidated the molecular mechanism behind the clock and hormone regulation of KLF9. Lentiviral knockdown and overexpression of KLF9 in three distinct breast epithelial cell lines (MCF10A, MCF7 and MDA-MB-231) was generated to demonstrate the role of KLF9 in orthogonal assays on breast epithelial survival, proliferation, apoptosis, and migration. Results We determined that KLF9 is a direct GC receptor target in mammary epithelial cells, and that induction is likely mediated through coordinate transcriptional activation from multiple GC-responsive enhancers in the KLF9 locus. More interestingly, rhythmic expression of KLF9 in MCF10A cells was abolished in the highly aggressive MDA-MB-231 line. In turn, forced expression of KLF9 altered the baseline and GC/E2-responsive expression of several clock genes, indicating that KLF9 may function as a regulator of the core clock machinery. Characterization of the role of KLF9 using complementary cancer hallmark assays in the context of the hormone-circadian axis revealed that KLF9 plays a tumor-suppressive role in BCa regardless of molecular subtype. KLF9 potentiated the anti-tumorigenic effects of GC in E2 receptor + luminal MCF7 cells, while it restrained GC-enhanced oncogenicity in triple-negative MCF10A and MDA-MB-231 cells. Conclusions Taken together, our findings support that dysregulation of KLF9 expression and oscillation in BCa impinges on circadian network dynamics, thus ultimately affecting the BCa oncogenic landscape.

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Section: Discussionmentioning

confidence: 99%

Krüppel-like factor 9 (KLF9) links hormone dysregulation and circadian disruption to breast cancer pathogenesis

Ybañez

Bagamasbad

2023

Cancer Cell Int

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“…Interestingly, a small but notable subset of sites were Dex-inducible in both ARID1a knockdown and control cells, and many of these were within loci containing genes found to be similarly Dex-regulated in control siRNA and ARID1a knockdown cells in the RNA-Seq analysis. Examples of genes that were in loci found to undergo Dex-inducible chromatin remodeling and Dex-dependent mRNA induction, in both ARID1a knockdown and control cells, included KLF9 [ 54 , 55 ], DDIT4 [ 56 ], GADD45a [ 57 ], and SERPINB [ 58 , 59 ], which are all important for cell proliferation and/or cell cycle regulation and have therefore also been grouped together with P53-regulated pathways, again supporting our conclusions of a selective effect of ARID1a knockdown.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel GR-ARID1a-P53BP1 protein complex involved in DNA damage repair and cell cycle regulation

et al. 2022

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ARID1a (BAF250), a component of human SWI/SNF chromatin remodeling complexes, is frequently mutated across numerous cancers, and its loss of function has been putatively linked to glucocorticoid resistance. Here, we interrogate the impact of siRNA knockdown of ARID1a compared to a functional interference approach in the HeLa human cervical cancer cell line. We report that ARID1a knockdown resulted in a significant global decrease in chromatin accessibility in ATAC-Seq analysis, as well as affecting a subset of genome-wide GR binding sites determined by analyzing GR ChIP-Seq data. Interestingly, the specific effects on gene expression were limited to a relatively small subset of glucocorticoid-regulated genes, notably those involved in cell cycle regulation and DNA repair. The vast majority of glucocorticoid-regulated genes were largely unaffected by ARID1a knockdown or functional interference, consistent with a more specific role for ARID1a in glucocorticoid function than previously speculated. Using liquid chromatography-mass spectrometry, we have identified a chromatin-associated protein complex comprising GR, ARID1a, and several DNA damage repair proteins including P53 binding protein 1 (P53BP1), Poly(ADP-Ribose) Polymerase 1 (PARP1), DNA damage-binding protein 1 (DDB1), DNA mismatch repair protein MSH6 and splicing factor proline and glutamine-rich protein (SFPQ), as well as the histone acetyltransferase KAT7, an epigenetic regulator of steroid-dependent transcription, DNA damage repair and cell cycle regulation. Not only was this protein complex ablated with both ARID1a knockdown and functional interference, but spontaneously arising DNA damage was also found to accumulate in a manner consistent with impaired DNA damage repair mechanisms. Recovery from dexamethasone-dependent cell cycle arrest was also significantly impaired. Taken together, our data demonstrate that although glucocorticoids can still promote cell cycle arrest in the absence of ARID1a, the purpose of this arrest to allow time for DNA damage repair is hindered.

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“…However, several previous studies have shown that KLF9 is overexpressed in hyperglycemia [30][31][32]. Contrariwise, KLF9's role as a tumor suppressor was con rmed in several cancers like prostate and gastric cancer [33,34].…”

Section: Discussionmentioning

confidence: 99%

The correlation between promoter methylation status and expression of KLF9 and MYH11 in Schizophrenia

Davarinejad

Foruzandeh

Golmohammadi

et al. 2022

Preprint

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In the current study, Methylation and expression microarray data related to Schizophrenia (SCZ) were analyzed to identify genes whose aberrant promoter methylation could play a crucial role in the dysregulation of gene expression. After data analysis, two genes including KLF9 and MYH11 were identified. Considering CpG sites in the promoter region of the mentioned genes using Methprimer database, Bisulfite specific primer (BSP) was designed, and Methylation specific-high resolution melting (MS-HRM) analysis was performed to assess the promoter methylation status of the genes, and also real-time PCR was used to evaluate mRNA expression level of KLF9 and MYH11 in 50 SCZ and healthy control specimens. The results show 62% hypermethylation and 38% hypomethylation of KLF9 in SCZ samples and 34% hypermethylation and 66% hypomethylation in healthy control samples. MYH11 promoter shows 54% hypermethylation and 46% hypomethylation in SCZ samples while 28% hypermethylation and 72% hypomethylation in healthy controls. The result of real-time PCR shows downregulation of KLF9 and MYH11 in SCZ samples compared with healthy samples. The aberrant methylation has a direct effect on the expression of mentioned genes.

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KLF9 suppresses cell growth and induces apoptosis via the AR pathway in androgen-dependent prostate cancer cells

Cited by 8 publications

References 27 publications

Krüppel-like factor 9 (KLF9) links hormone dysregulation and circadian disruption to breast cancer pathogenesis

Krüppel-like factor 9 (KLF9) links hormone dysregulation and circadian disruption to breast cancer pathogenesis

Identification of a novel GR-ARID1a-P53BP1 protein complex involved in DNA damage repair and cell cycle regulation

The correlation between promoter methylation status and expression of KLF9 and MYH11 in Schizophrenia

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