Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2023
Höfundar / Authors: Kristinn Ragnar Óskarsson, Magnús Arnar Rúnarsson og Pétur Orri Heiðarsson
Starfsvettvangur / Affiliations: 1. University of Iceland
Kynnir / Presenter: Kristinn Ragnar Óskarsson
FOXA1 is a pioneer transcription factor with chromatin remodeling activity and is also a key regulator of hormone nuclear receptors in various tissues. FOXA1 plays a critical role in the progression and prognosis of nuclear receptor positive cancers that develop in the mammary gland and prostate. The protein is enriched in structurally disordered regions that are of interest as a mutational hotspot is found in the unstructured Wing2 subdomain. Mutations in Wing2 subdomain are enriched both in mammary gland and prostate tumors that can develop resistance against endocrine therapies. We have observed how mutations in the Wing2 subdomain change the structural ensemble of FOXA1 around the DNA binding domain (DBD) using single molecular spectroscopy. Notably the mutation S250F located on the Wing2 subdomain of FOXA1 showed an increased compaction around the DBD that might be key to its modified transcriptional activity. These results might be the first step in understanding how mutations in FOXA1 contribute to the ability of nuclear receptor positive cancer cells to proliferate when deprived of hormones, and thus, a step in battling endocrine therapy resistant tumors in the prostate and mammary gland.