Downregulation of ARHGAP25 was found in the tumor samples from breast cancer patients and five breast cancer cell lines. However, its precise role and molecular mechanisms in breast cancer remain completely unknown. Herein, we found that knockdown of ARHGAP25 in breast cancer cells promoted proliferation, migration and invasion of breast cancer cells. Mechanistically, ARHGAP25 silence facilitated the activation of the Wnt/β-catenin pathway and the upregulation of its downstream molecules (including c-Myc, Cyclin D1, PCNA, MMP2, MMP9, Snail, and ASCL2) by directly regulating Rac1/PAK1 in breast cancer cells. In vivo xenograft experiments indicated ARHGAP25 silence promoted tumor growth and activated the Wnt/β-catenin pathway. In contrast, overexpression of ARHGAP25 in vitro and in vivo impeded all of the above cancer properties. Intriguingly, ASCL2, a downstream target of the Wnt/β-catenin pathway, transcriptionally repressed the expression of ARHGAP25 and therefore constituted a negative feedback loop. Moreover, bioinformatics analysis indicated that ARHGAP25 is significantly correlated with tumor immune cell infiltration and the survival of patients with different immune cell subgroups in breast cancer. Collectively, our work revealed that ARHGAP25 suppressed tumor progression of breast cancer. It provides a novel insight for the treatment of breast cancer.
Qigen Fang,Xu Zhang,Junhui Yuan,Liyuan Dai,Mingwei Su
Achaete-scute homolog 2 (ASCL2), as a transcription factor, is overexpressed in various tumors and considered to be associated with malignant progression and poor prognosis of tumors. However, whether ASCL2 affects head and neck squamous cell carcinoma (HNSCC) progression has not been studied. We reported that ASCL2 was up-regulated in HNSCC tumor tissues compared to normal tissues, and that this increase was associated with adverse clinical outcomes. Cell-based characteristics revealed the pro-oncogenic effect of ASCL2 overexpression in cell proliferation, colony formation, sphere growth and migration/invasion through facilitating epithelial-mesenchymal transition (EMT). Knocking down ASCL2 resulted in growth arrest of HNSCC cells and the inhibition of malignant behaviors. The xenograft tumor model of ASCL2-expressing cells was larger, more prone to lymph node metastasis (LNM), and exhibited more significant characteristics of cancer stem cells (CSCs) (upregulated CD44, OCT4, and NANOG and increased stem cell frequency). Analysis between mRNA-seq and ChIP-seq showed that ASCL2 regulated the function of SNF2 histone-linker PHD-finger RING-finger helicase (SHPRH). SHPRH was inhibited in ASCL2-expressed HNSCC cells. Mechanistically, ASCL2 suppressed the transcriptional activity of SHPRH, subsequently leading to a weakened ability of SHPRH in inhibiting the proliferation, migration, invasion. Overexpressing SHPRH in ASCL2-expressed HNSCC cells alleviated the malignant behavior of tumor cells. In conclusion, our research revealed that ASCL2 promoted the proliferation, EMT and CSC characteristics of HNSCC cells by transcriptionally inhibiting the expression of SHPRH. Targeting this process might be a promising approach for HNSCC therapy.
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