Grainyhead-like transcription factors in cancer - Focus on recent developments

The role of grainyhead-like transcription factors in cancer has been widely investigated by the scientific community. However, some of its aspects do not seem to be adequately appreciated, and these are the topic of our article. In addition to their well-documented role as tumor suppressors, in many cases the grainyhead-like proteins perform tumor-promoting functions, which make them potential drug targets. However, it is difficult to directly target transcription factors, which is why we recommend an alternative approach. The transcriptional transactivation activity of grainyhead-like transcription factors is regulated by phosphorylation, and protein kinases are much more feasible drug targets. Studying the phosphorylation of grainyhead-like proteins may thus allow to identify protein kinases regulating the activity of these factors, and design inhibitors of these kinases to indirectly regulate the activity of grainyhead-like transcription factors. There are many somatic mutations in the GRHL genes that occur during cancer development. These mutations are widely distributed across the GRHL loci, and these mutations are very rare. For this reason, they are unlikely to become targets of future therapies, nevertheless some of them may be driver mutations and studying them may provide important novel information about the regulation of functioning of the GRHL genes and proteins. Analogous information may be obtained by studying single nucleotide polymorphisms in GRHL genes that are associated with disease risk. Such polymorphisms may also prove useful in identifying individuals with an increased risk of a particular disease.

Impact statement: In the present article, we focus on relatively little appreciated aspects of involvement of the grainyhead-like (GRHL) transcription factors in cancer. These aspects are nevertheless very important for the functioning of GRHL proteins, as well as for cancer development. Some of the GRHL factors perform tumor-promoting functions in certain types of cancer, which makes them potential drug targets. Much information is available about somatic cancer mutations in the GRHL genes, yet there are very few analyses of these mutations in the scientific literature. The activity of GRHL transcription factors is controlled by phosphorylation, and we suggest that regulating their phosphorylation with specific protein kinases provides an alternative approach to modify the activity of GRHL proteins. Some single nucleotide polymorphisms (SNPs) in the GRHL genes are associated with disease risk. Studying such SNPs may yield new information about the functioning of GRHL genes and proteins, and may also allow to identify people with an increased risk of a particular disease.