ASCL2 promotes malignant progression in head and neck squamous cell carcinoma by transcriptionally downregulating SHPRH.

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.