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.

• Authors: Ying Z Mazzu, YuRou Liao, Subhiksha Nandakumar, Martin Sjöström, Lina E Jehane, Romina Ghale, Barani Govindarajan, Travis A Gerke, Gwo-Shu Mary Lee, Jian-Hua Luo, Sreenivasa R Chinni, Lorelei A Mucci, Felix Y Feng, Philip W Kantoff
• Journal: Molecular oncology (Mol Oncol) Vol. 16 Issue 13 Pg. 2451-2469 (07 2022) ISSN: 1878-0261 [Electronic] United States
• PMID: 34792282 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• Oncogene Proteins, Fusion
• SNAI2 protein, human
• Snail Family Transcription Factors
• Panobinostat
• Dasatinib

Topics

• Cell Line, Tumor
• Dasatinib (therapeutic use)
• Humans
• Male
• Oncogene Proteins, Fusion (genetics)
• Panobinostat (therapeutic use)
• Prostatic Neoplasms (drug therapy, genetics)
• Snail Family Transcription Factors (genetics)
• Tumor Microenvironment