ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease treatment. Anoctamin 1 (ANO1) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27Kip1 expression. Suppressing ANO1 expression led to redistribution of p27Kip1 from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target.

Investigation of an FGFR-Signaling-Related Prognostic Model and Immune Landscape in Head and Neck Squamous Cell Carcinoma

“…Though the activation of the p-ERK pathway, SEMA3C promotes cervical cancer growth, which is related to poor prognosis ( Liu et al, 2019a ). ANO1 encodes a calcium-dependent chloride channel protein and commonly amplifies to facilitate several cancers’ progression, including ovarian ( Liu et al, 2019b ), prostate ( Liu et al, 2012 ), breast ( Britschgi et al, 2013 ), and head and neck cancers ( Filippou et al, 2021 ). After neoadjuvant chemoradiotherapy, the expression level of IGHG2 increased significantly in rectal cancer, indicating that IGHG2 was originally with a low expression in tumor cells and existed as a protective factor, which was consistent with our prognostic analysis.…”

ANO1: More Than Just Calcium-Activated Chloride Channel in Cancer

“…At the same time, research on colorectal cancer found that cyclin D1 protein expression was positively correlated with ERK1/2 and ANO1.ANO1 inhibits G1 to S phase progression by down-regulating the expression of the ANO1, which is consistent with the decreased expression of cyclin D1 ( 28 ). Suppressing ANO1 expression also had significantly lower cyclin D1, leading to changes in p27 Kip1 distribution and correlated with a cell cycle arrest phenotype in HNSCC ( 8 , 73 ).…”

Global impact of somatic structural variation on the cancer proteome

“…Out of 517 CGI methylation probes negatively correlated with nearby SV breakpoints, 50 involved genes positively correlated between mRNA and SV breakpoints (overlap p < 1E−4, chi-squared test), of which 21 CGI probes involved positive correlations at the protein level. Genes involving SV-associated lower CGI methylation with concordant protein and mRNA changes included NID2 50 and ANO1 51 (Fig. 5d ).…”