FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes

Abstract

Mutations in the FOXA1 transcription factor define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. By annotating the FOXA1 mutation landscape from 3086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (~50% of all mutations) and R219 (~5%), a highly conserved DNA contact residue. Clinically, Wing2 mutations are seen in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumors with neuroendocrine histology. Interrogation of the biologic properties of FOXA1WT and 14 FOXA1 mutants revealed gain-of-function in mouse prostate organoid proliferation assays. 12 of these mutants, as well as FOXA1WT, promoted an exaggerated pro-luminal differentiation program whereas two different R219 mutants blocked luminal differentiation and activate a mesenchymal and neuroendocrine transcriptional program. ATAC-seq of FOXA1WT and representative Wing2 and R219 mutants revealed dramatic, mutant-specific changes in open chromatin at thousands of genomic loci, together with novel sites of FOXA1 binding and associated increases in gene expression. Of note, peaks in R219 mutant expressing cells lack the canonical core FOXA1 binding motifs (GTAAAC/T) but are enriched for a related, non-canonical motif (GTAAAG/A), which is preferentially activated by R219 mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its normal pioneering function through perturbation of normal luminal epithelial differentiation programs, providing further support to the role of lineage plasticity in cancer progression.

The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

“…A number of families whose members are responsible for genetic diseases or cancers in humans are indicated in Figure 1. FOXO genes are rearranged in various cancers [16,17]; FOXA1 is mutated in prostate and breast tumors [18][19][20][21], while FOXM1 has been shown to be a potent outcome predictor in various cancer types [22].…”

Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

“…Sequencing efforts identified coding somatic single-nucleotide variants (SNVs) mapping to FOXA1 in up to 9% [5][6][7][8][9][10] and 13% [9][10][11] of primary and mCRPC patients, respectively. These coding somatic SNVs target the Forkhead and transactivation domains of FOXA1 12 , altering its pioneering functions to promote prostate cancer development 10,13 . Outside of coding SNVs, whole-genome sequencing also identified somatic SNVs and indels in the 3'UTR and C-terminus of FOXA1 in~12% of mCPRC patients 14 .…”

“…Outside of coding SNVs, whole-genome sequencing also identified somatic SNVs and indels in the 3'UTR and C-terminus of FOXA1 in~12% of mCPRC patients 14 . In addition to SNVs, the FOXA1 locus is a target of structural rearrangements in both primary and metastatic prostate cancer tumors, inclusive of duplications, amplifications, and translocations 9,10 . Taken together, FOXA1 is recurrently mutated taking into account both its coding and flanking noncoding sequences across various stages of prostate cancer development.…”

P53‐regulated lncRNA uc061hsf.1 inhibits cell proliferation and metastasis in human esophageal squamous cell cancer

“…Previous studies have found that FoxA1 was as an oncogene, which had a negative correlated with tumor invasion and metastasis in breast, prostate cancers . However, FOXA1 mutations occurred frequently in many cancers and were associated with a worse clinical outcome, including tumor invasion and metastasis . In this article, we found that uc061hsf.1 was able to negative control the expression of FoxA1, suggesting that the function of uc061hsf.1 may be to inhibit tumor proliferation and invasion through suppresses FoxA1.…”

“…32,33 However, FOXA1 mutations occurred frequently in many cancers and were associated with a worse clinical outcome, including tumor invasion and metastasis. 34,35 In this article, we found that uc061hsf.1 was able to negative control the expression of FoxA1, suggesting that the function of uc061hsf.1 may be to inhibit tumor proliferation and invasion through suppresses FoxA1. We have thus provided preliminary evidence in support of FoxA1 as downstream target of uc061hsf.1, thus offering novel insight into the molecular mechanisms whereby this lncRNA regulates ESCC.…”