BTK isoforms p80 and p65 are expressed in head and neck squamous cell carcinoma (HNSCC) and involved in tumor progression

Background Bruton’s Tyrosine Kinase (BTK) belongs to the Tec family of non-receptor tyrosine kinases and was originally considered to be primarily expressed in cells of the hematopoietic origin. Apart from the 77 kDa BTK isoform expressed in immune cells, elevated expression of novel BTK isoforms of 80 and 65 kDa have been recently described for several solid tumor entities. The present study aims to investigate whether these BTK isoforms are also expressed in HNSCC and its molecular consequences for tumorigenesis.

Methods HNSCC cell lines and primary tumor tissue were analyzed for BTK-p65 and -p80 expression. Potential effects of BTK inhibition on proliferation, cell cycle, apoptosis, autophagy, migration, tumor growth and vascularization were addressed in vitro and in vivo. Possible regulation of the BTK-p65/-p80 expression by methylation was evaluated by analyzing a TCGA dataset.

Results We identified the newly described oncogenic BTK-p80 and -p65 isoforms in HNSCC cell lines and primary HNSCC tissue. Chemical or genetic abrogation of BTK activity impaired proliferation, migration and induced cell cycle arrest, apoptosis as well as autophagy in HNSCC cell lines. Moreover, BTK inhibition impaired tumor growth and angiogenesis in vivo. Methylation analysis revealed a significant reduction in the methylation level in HNSCC tumors compared to paired healthy mucosa for six CpG loci.

Conclusions Our data characterize BTK-p65 and BTK-p80 isoforms as novel HNSCC-associated oncogenes promoting HNSCC cell survival. Our epigenetic analysis suggests that the alternative promoter of BTK-p80/p65 could be regulated by methylation. Altogether, targeting BTK activity appears as a promising therapeutic option for patients suffering from BTK expressing HNSCC.

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Artikel online veröffentlicht:
12. Mai 2023