Frequent aberrant expression of the human ether à go-go (hEAG1) potassium channel in head and neck cancer: pathobiological mechanisms and clinical implications

Abstract

Compelling evidence indicates that the human ether-à-go-go voltage-gated potassium channels (hEAG1) may represent new valuable membrane therapeutic targets and diagnostic/prognostic biomarkers in various cancers. This study is the first to investigate the expression of hEAG1 potassium channel subunit in both primary tumors and HNSCC-derived cell lines to ascertain its clinical and biological role in tumor progression. Our findings demonstrate that hEAG1 is frequently aberrantly expressed in a high percentage of primary tumors (83 %, 45/54 cases) and HNSCC-derived cell lines (83 %, 10/12 cell lines). hEAG1 expression increased during HNSCC progression and was more frequent in advanced tumors. Strikingly, hEAG1 expression was also detected in a notable proportion (39 %, 17/44 cases) of patient-matched normal adjacent mucosa, whereas no expression was detected in normal epithelia from non-oncologic patients without exposure to tobacco carcinogens. In an attempt to identify the underlying mechanisms of aberrant hEAG1 expression in HNSCC, we found that hEAG1 gene copy gain occurred at a low frequency (15 %, 13/88 cases) in primary tumors but was not observed in early stages of HNSCC tumorigenesis. Furthermore, this study provides original evidence supporting the involvement of histone acetylation (i.e., H3Ac and H4K16Ac activating marks) in the regulation of hEAG1 expression in HNSCC. In addition, functional studies in HNSCC cells further revealed that hEAG1 expression is a biologically relevant feature that promotes cell proliferation and invasion, although independently of its ion-conducting function. Our findings strongly support the notion that hEAG1 may represent a promising candidate as tumor marker and membrane therapeutic target for HNSCC treatment.

Positive correlation between the expression of hEag1 and HIF-1α in breast cancers: an observational study

“…The disease-free and overall 6-year survival rates were reported to have increased twofold in patients with cervical cancer with well-oxygenated tumours 14. Similar results occurred in head and neck cancer24 and soft tissue sarcomas 38. Eag1 was expressed in all three well-oxygenated tumour types.…”

“…Eag1 expression is positively correlated with some clinical parameters, such as tumour size in head and neck cancer24 and lymph node metastases in colorectal cancer 25. Eag1 expression was associated with clinical parameters in different categories of cancer, including epithelial origin cancers and non-epithelial origin ones.…”

Potassium channels in cell cycle and cell proliferation

“…It had been assumed that K V 10.1 is present only in solid tumours but recent research has revealed its presence in leukaemias, correlating with a poor prognosis [107]. K V 10.1 expression also correlates with poor prognosis for patients of ovarian [106], gastric [112] and colon cancer [114], and with lymph node metastasis in gastric cancer and head and neck squamous cell carcinoma, where it also correlates with the disease stage [105]. Moreover, a number of studies have supported the observation that K V 10.1 blockage or knockdown decreases the proliferation of many cancer cell lines and in vivo tumour models [53,107,115,116].…”

Targeting potassium channels in cancer

“…Dysregulation of potassium channel expression has been identified at genomic, transcriptional, posttranslational, and epigenetic levels. For example, KCNK9 is amplified from 3- to 10-fold in 10% of breast tumors (Mu et al, 2003), and genomic amplification of EAG1 was found in 15% of head and neck carcinoma (Menéndez et al, 2012) and 3.4% of human colorectal adenocarcinoma (Ousingsawat et al, 2007). Estrogen treatment can up-regulate Kir channel transcription in human breast cancer cells to promote proliferation (Williams et al, 2008).…”