Dynamic expression of SNAI2 in prostate cancer predicts tumor progression and drug sensitivity
Abstract
Prostate cancer is a highly heterogeneous disease, understanding the crosstalk between complex genomic and epigenomic alterations will aid in developing targeted therapeutics. We demonstrate that, even though snail family transcriptional repressor 2 (SNAI2) is frequently amplified in prostate cancer, it is epigenetically silenced in this disease, with dynamic changes in SNAI2 levels showing distinct clinical relevance. Integrative clinical data from 18 prostate cancer cohorts and experimental evidence showed that gene fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2–ERG fusion) is involved in the silencing of SNAI2. We created a silencer score to evaluate epigenetic repression of SNAI2, which can be reversed by treatment with DNA methyltransferase inhibitors and histone deacetylase inhibitors. Silencing of SNAI2 facilitated tumor cell proliferation and luminal differentiation. Furthermore, SNAI2 has a major influence on the tumor microenvironment by reactivating tumor stroma and creating an immunosuppressive microenvironment in prostate cancer. Importantly, SNAI2 expression levels in part determine sensitivity to the cancer drugs dasatinib and panobinostat. For the first time, we defined the distinct clinical relevance of SNAI2 expression at different disease stages. We elucidated how epigenetic silencing of SNAI2 controls the dynamic changes of SNAI2 expression that are essential for tumor initiation and progression and discovered that restoring SNAI2 expression by treatment with panobinostat enhances dasatinib sensitivity, indicating a new therapeutic strategy for prostate cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 11, 2022
- Source ID
- 10.1002/1878-0261.13140
Entities
People
- Barani Govindarajan
- Felix Y. Feng
- Gwo‐Shu Mary Lee
- Jian‐hua Luo
- Lina E. Jehane
- Lorelei A. Mucci
- Martin Sjöström
- Philip W. Kantoff
- Romina Ghale
- Sreenivasa R. Chinni
- Subhiksha Nandakumar
- Travis A. Gerke
- Ying Z. Mazzu
- Yurou Liao
Organizations
- Dana–Farber Cancer Institute
- Harvard University
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- United States Department of Defense
- University of California, San Francisco
- University of Pittsburgh
- Wayne State University