Novel mechanistic targets of Forkhead box Q1 transcription factor in human breast cancer cells

Cancer Prevention Research

Hahm

et al. 2021

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Elimination of both rapidly dividing epithelial mammary cancer cells as well as breast cancer stem-like cells (bCSC) is essential for maximizing antitumor response. Withaferin A (WA), a small molecule derived from a medicinal plant (Withania somnifera), is highly effective in reducing burden and/or incidence of breast cancer in vivo in various preclinical models. We have shown previously that suppression of breast cancer incidence by WA administration in a rat model is associated with a decrease in self-renewal of bCSC but the underlying mechanism is still elusive. This study investigated the role of forkhead box Q1 (FoxQ1) transcription factor in antitumor responses to WA. Exposure of MDA-MB-231 and SUM159 cells to WA resulted in downregulation of protein and mRNA levels of FoxQ1 as well as inhibition of its transcriptional activity. FoxQ1 overexpression in SUM159 and MCF-7 cells resulted in a marked protection against WA-mediated inhibition of bCSC as judged by flow cytometric analysis of CD49f high population and mammosphere assay. RNA-seq analysis revealed upregulation of many bCSCassociated genes by FoxQ1 overexpression in SUM159 cells, including interleukin-8 (IL-8) whose expression was decreased by WA treatment in SUM159 and MCF-7 cells. FoxQ1 was recruited to the promoter of IL-8 that was inhibited significantly by WA treatment. On the other hand, WAmediated inhibition of cell proliferation or migration was not affected by FoxQ1 overexpression. The FoxQ1 overexpression partially attenuated WA-mediated G 2 /M phase cell cycle in SUM159 cells only. These results indicate that FoxQ1 is a target of WA for inhibition of bCSC fraction.

Section: Discussionmentioning

confidence: 71%

Section: The Bcsc-associated Genes Downregulated By Wa Treatment In Breast Cancer Cellsmentioning

confidence: 95%

Section: Wa Treatment Inhibited Il-8 Level In Breast Cancer Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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The Role of Forkhead Box Q1 Transcription Factor in Anticancer Effects of Withaferin A in Breast Cancer

Cancer Prevention Research

Hahm

et al. 2021

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“…7 Overexpression of FoxQ1 has been reported in basal-like and luminal-type human breast cancers in comparison with normal mammary tissues. 8,9 An oncogenic function of FoxQ1 in breast cancer was first reported by Zhang et al 10 in regulation of epithelial-mesenchymal transition (EMT) through cross-species gene expression profiling strategy. Overexpression of FoxQ1 in HMLE cells resulted in increased cell migration and invasion in vitro, whereas knockdown of this protein in the 4T1 mouse mammary carcinoma cell line reversed these effects.…”

mentioning

confidence: 99%

The FoxQ1 transcription factor is a novel regulator of electron transport chain complex I subunits in human breast cancer cells

Molecular Carcinogenesis

2021

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The FoxQ1 is an oncogenic transcription factor that is overexpressed in basal-like and luminal-type human breast cancers when compared to the normal mammary tissue. The FoxQ1 is implicated in mammary tumor progression. However, the mechanism by which FoxQ1 promotes mammary tumorigenesis is not fully understood. In this study, we present experimental evidence for a novel function of FoxQ1 in the regulation of complex I activity of the electron transport chain. The RNA-seq data from FoxQ1 overexpressing basal-like SUM159 cells revealed a statistically significant increase in the expression of complex I subunits NDUFS1 and NDUFS2 when compared to the empty vector (EV) transfected control cells.Consistent with these results, the basal and ATP-linked oxygen consumption rates were significantly increased by FoxQ1 overexpression in SUM159 and luminal-type MCF-7 cells. The FoxQ1 overexpression in both cell lines resulted in increased intracellular levels of pyruvate, lactate, and ATP that was associated with overexpression of pyruvate dehydrogenase and pyruvate carboxylase proteins. Activity and assembly of complex I were significantly enhanced by FoxQ1 overexpression in SUM159 and MCF-7 cells that correlated with increased mRNA and/or protein levels of complex I subunits NDUFS1, NDUFS2, NDUFV1, and NDUFV2. The chromatin immunoprecipitation assay revealed the recruitment of FoxQ1 at the promoters of both NDUFS1 and NDUFV1. The cell proliferation of SUM159 and MCF-7 cells was increased significantly by overexpression of NDUFS1 as well as NDUFV1 proteins. In conclusion, we propose that increased complex I-linked oxidative phosphorylation is partly responsible for oncogenic role of FoxQ1 at least in human breast cancer cells.

Monocarboxylate transporter 1 is a novel target for breast cancer stem like‐cell inhibition by diallyl trisulfide

Molecular Carcinogenesis

2022

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Diallyl trisulfide (DATS) is a promising small molecule phytochemical that exhibits in vitro and in vivo activity in multiple preclinical solid tumor models including breast cancer, but the underlying mechanism is not fully understood.We have shown previously that forkhead box Q1 (FoxQ1) transcription factor is a novel target for breast cancer stem-like cells (bCSC) inhibition by DATS.Analysis of the breast TCGA (The Cancer Genome Atlas) data revealed that FoxQ1 expression was positively associated with that of SLC16A1/monocarboxylate transporter 1 (MCT1). Western blot analysis confirmed increased expression of MCT1 protein in SUM159 (basal-like) and MCF-7 cells (luminal-type) stably transfected to overexpress FoxQ1. Furthermore, FoxQ1 was recruited to the promoter of SLC16A1/MCT1. Treatment of SUM159 and MCF-7 cell lines with DATS resulted in suppression of MCT1 protein level that was accompanied by a decrease in intracellular and secreted levels of lactate. Overexpression or knockdown of MCT1 protein failed to alter DATS-mediated inhibition of colony formation or cell migration when compared to corresponding control cells. On the other hand, overexpression of MCT1 protein conferred partial but statistically significant protection against DATS-mediated inhibition of bCSC fraction (CD49f high /CD44 high and aldehyde dehydrogenase 1 activity). The size of the mammospheres was relatively smaller in the DATS-treated group compared to control group. Inhibition of bCSC upon DATS treatment was augmented by knockdown of the MCT1 protein. In conclusion, the present study reveals that MCT1 is a novel target for bCSC inhibition by DATS treatment.