ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy

Abstract

The nine identified human homologues of E. coli AlkB 2-oxoglutarate (2OG) and Fe(II)-dependent dioxygenase, ALKBH1-8 and FTO, display different substrate specificities and diverse biological functions. Here we discovered the combined overexpression of members of the ALKBH family in head and neck squamous cell carcinomas (HNSCC). We found direct correlation of ALKBH3 and FTO expression with primary HNSCC tumor size. We observed unidentified thus far cytoplasmic localization of ALKBH2 and 5 in HNSCC, suggesting abnormal role(s) of ALKBH proteins in cancer. Further, high expression of ALKBHs was observed not only in HNSCC, but also in several cancerous cell lines and silencing ALKBH expression in HeLa cancer cells resulted in dramatically decreased survival. Considering the discovered impact of high expression of ALKBH proteins on HNSCC development, we screened for ALKBH blockers among newly synthetized anthraquinone derivatives and demonstrated their potential to support standard anticancer therapy.

Human and Arabidopsis alpha‐ketoglutarate‐dependent dioxygenase homolog proteins—New players in important regulatory processes

“…It associates with the activating signal cointegrator 1 complex subunit 3 of activating signal cointegrator complex thus being involved in the generation of ssDNA, to maintain genomic integrity . As in the case of ALKBH2, ALKBH3 is also overexpressed in different cancers, for example, rectal carcinoma, pancreatic cancer, head and neck squamous cell carcinoma (HNSCC), and others . The aforementioned information, with findings that knockdown of the ALKBH3 gene leads to a decrease in the diameter of tumor in mice, strongly suggest that ALKBH3 repair activity is necessary for tumor maintenance …”

“…Additionally, ALKBH2 shows an important role in maintaining the rDNA gene integrity and transcription . It is worth mentioning that ALKBH2 promotes cancer development …”

“…Similar to ALKBH5, FTO is an RNA demethylase, removing the methyl group from modified adenosine . Up to now, it is known that FTO is involved in many biological processes, for example, cancer development, adipogenesis, or bone growth …”

“…In melanoma, tumorigenesis is caused by specific demethylation of mRNA of programmmed cell death protein 1, C‐X‐C chemokine receptor 4, and transcription factor SOX‐10. Moreover, for AML, gastric, endometrial, or HNSCC, this protein is involved in cancer development . An elevated FTO level is also responsible for chemotherapy resistance of cervical squamous cell carcinoma (Figure ).…”

Intracellular and tissue specific expression of FTO protein in pig: changes with age, energy intake and metabolic status

“…Studies in mice model indicate that there is a positive correlation between the expression of FTO protein and body weight 7 . It has been suggested that FTO may directly regulate food intake, fat development, energy metabolism, cell proliferation, and cancer development [30][31][32][33][34][35][36][37][38] . It has also been found that the availability of glucose and amino acids regulates FTO protein expression: glucose/amino acid starvation leads to a decrease in the level of FTO protein 39 .…”