Author
Listed:
- Abhijit Parolia
(University of Michigan
University of Michigan
University of Michigan)
- Marcin Cieslik
(University of Michigan
University of Michigan
University of Michigan)
- Shih-Chun Chu
(University of Michigan
University of Michigan)
- Lanbo Xiao
(University of Michigan
University of Michigan)
- Takahiro Ouchi
(University of Michigan
University of Michigan)
- Yuping Zhang
(University of Michigan
University of Michigan)
- Xiaoju Wang
(University of Michigan
University of Michigan)
- Pankaj Vats
(University of Michigan
University of Michigan)
- Xuhong Cao
(University of Michigan
University of Michigan
University of Michigan)
- Sethuramasundaram Pitchiaya
(University of Michigan
University of Michigan)
- Fengyun Su
(University of Michigan
University of Michigan)
- Rui Wang
(University of Michigan
University of Michigan)
- Felix Y. Feng
(University of California at San Francisco
University of California at San Francisco
University of California at San Francisco
University of California at San Francisco)
- Yi-Mi Wu
(University of Michigan
University of Michigan)
- Robert J. Lonigro
(University of Michigan
University of Michigan)
- Dan R. Robinson
(University of Michigan
University of Michigan)
- Arul M. Chinnaiyan
(University of Michigan
University of Michigan
University of Michigan
University of Michigan)
Abstract
Abtract Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours3–8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive9–11 and oncogenic12–14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and—through TLE3 inactivation—promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element—herein denoted FOXA1 mastermind (FOXMIND)—to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.
Suggested Citation
Abhijit Parolia & Marcin Cieslik & Shih-Chun Chu & Lanbo Xiao & Takahiro Ouchi & Yuping Zhang & Xiaoju Wang & Pankaj Vats & Xuhong Cao & Sethuramasundaram Pitchiaya & Fengyun Su & Rui Wang & Felix Y. , 2019.
"Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer,"
Nature, Nature, vol. 571(7765), pages 413-418, July.
Handle:
RePEc:nat:nature:v:571:y:2019:i:7765:d:10.1038_s41586-019-1347-4
DOI: 10.1038/s41586-019-1347-4
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Citations
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Cited by:
- 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.
- 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.
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