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FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes

Author

Listed:
  • Elizabeth J. Adams

    (Memorial Sloan Kettering Cancer Center)

  • Wouter R. Karthaus

    (Memorial Sloan Kettering Cancer Center)

  • Elizabeth Hoover

    (Memorial Sloan Kettering Cancer Center)

  • Deli Liu

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medical College)

  • Antoine Gruet

    (Memorial Sloan Kettering Cancer Center)

  • Zeda Zhang

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Hyunwoo Cho

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School)

  • Rose DiLoreto

    (Weill Cornell Graduate School
    Weill Cornell Medicine)

  • Sagar Chhangawala

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School)

  • Yang Liu

    (GenomeDx Bioscience)

  • Philip A. Watson

    (Memorial Sloan Kettering Cancer Center)

  • Elai Davicioni

    (GenomeDx Bioscience)

  • Andrea Sboner

    (Weill Cornell Medicine
    Weill Cornell Medical College
    Englander Institute for Precision Medicine of Weill Cornell Medicine and NewYork-Presbyterian Hospital)

  • Christopher E. Barbieri

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Englander Institute for Precision Medicine of Weill Cornell Medicine and NewYork-Presbyterian Hospital)

  • Rohit Bose

    (University of California, San Francisco)

  • Christina S. Leslie

    (Weill Cornell Graduate School)

  • Charles L. Sawyers

    (Memorial Sloan Kettering Cancer Center
    Howard Hughes Medical Institute)

Abstract

Mutations in the transcription factor FOXA1 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. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.

Suggested Citation

  • Elizabeth J. Adams & Wouter R. Karthaus & Elizabeth Hoover & Deli Liu & Antoine Gruet & Zeda Zhang & Hyunwoo Cho & Rose DiLoreto & Sagar Chhangawala & Yang Liu & Philip A. Watson & Elai Davicioni & An, 2019. "FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes," Nature, Nature, vol. 571(7765), pages 408-412, July.
  • Handle: RePEc:nat:nature:v:571:y:2019:i:7765:d:10.1038_s41586-019-1318-9
    DOI: 10.1038/s41586-019-1318-9
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    Cited by:

    1. Chandrani Mukhopadhyay & Chenyi Yang & Limei Xu & Deli Liu & Yu Wang & Dennis Huang & Lesa Dayal Deonarine & Joanna Cyrta & Elai Davicioni & Andrea Sboner & Brian. D. Robinson & Arul M. Chinnaiyan & M, 2021. "G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Zifeng Wang & Scott L. Townley & Songqi Zhang & Mingyu Liu & Muqing Li & Maryam Labaf & Susan Patalano & Kavita Venkataramani & Kellee R. Siegfried & Jill A. Macoska & Dong Han & Shuai Gao & Gail P. R, 2024. "FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Alexandros Armaos & François Serra & Iker Núñez-Carpintero & Ji-Heui Seo & Sylvan C. Baca & Stefano Gustincich & Alfonso Valencia & Matthew L. Freedman & Davide Cirillo & Claudia Giambartolomei & Gian, 2023. "The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Jeroen Kneppers & Tesa M. Severson & Joseph C. Siefert & Pieter Schol & Stacey E. P. Joosten & Ivan Pak Lok Yu & Chia-Chi Flora Huang & Tunç Morova & Umut Berkay Altıntaş & Claudia Giambartolomei & Ji, 2022. "Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Joshua I. Warrick & Wenhuo Hu & Hironobu Yamashita & Vonn Walter & Lauren Shuman & Jenna M. Craig & Lan L. Gellert & Mauro A. A. Castro & A. Gordon Robertson & Fengshen Kuo & Irina Ostrovnaya & Judy S, 2022. "FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Ning Zhang & Luuk Harbers & Michele Simonetti & Constantin Diekmann & Quentin Verron & Enrico Berrino & Sara E. Bellomo & Gabriel M. C. Longo & Michael Ratz & Niklas Schultz & Firas Tarish & Peng Su &, 2024. "High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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