Epigenetic Suppression of SERPINB1 Promotes Inflammation-Mediated Prostate Cancer Progression

• Published in: Molecular cancer research 2019-04, Vol.17 (4), p.845-859
• Main Authors: Lerman, Irina, Ma, Xiaoting, Seger, Christina, Maolake, Aerken, Garcia-Hernandez, Maria de la Luz, Rangel-Moreno, Javier, Ackerman, Jessica, Nastiuk, Kent L, Susiarjo, Martha, Hammes, Stephen R
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Disease Progression; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; Histones - genetics; Histones - metabolism; Humans; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Male; Mice; Mice, Nude; Promoter Regions, Genetic; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serpins - genetics; Serpins - metabolism; Transfection
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-0638

Granulocytic myeloid infiltration and resultant enhanced neutrophil elastase (NE) activity is associated with poor outcomes in numerous malignancies. We recently showed that NE expression and activity from infiltrating myeloid cells was high in human prostate cancer xenografts and mouse -null prostate tumors. We further demonstrated that NE directly stimulated human prostate cancer cells to proliferate, migrate, and invade, and inhibition of NE attenuated xenograft growth. Interestingly, reduced expression of SERPINB1, an endogenous NE inhibitor, also correlates with diminished survival in some cancers. Therefore, we sought to characterize the role of SERPINB1 in prostate cancer. We find that SERPINB1 expression is reduced in human metastatic and locally advanced disease and predicts poor outcome. SERPINB1 is also reduced in -null mouse prostate tumors compared with wild-type prostates, and treatment with sivelestat (SERPINB1 pharmacomimetic) attenuates tumor growth. Knockdown of highly expressed SERPINB1 in nonmalignant prostatic epithelial cells (RWPE-1) increases proliferation, decreases apoptosis, and stimulates expression of epithelial-to-mesenchymal transition markers. In contrast, stable SERPINB1 expression in normally low-expressing prostate cancer cells (C4-2) reduces xenograft growth . Finally, EZH2-mediated histone (H3K27me3) methylation and DNA methyltransferase-mediated DNA methylation suppress SERPINB1 expression in prostate cancer cells. Analysis of The Cancer Genome Atlas and pyrosequencing demonstrate hypermethylation of the promoter in prostate cancer compared with normal tissue, and the extent of promoter methylation negatively correlates with mRNA expression. IMPLICATIONS: Our findings suggest that the balance between SERPINB1 and NE is physiologically important within the prostate and may serve as a biomarker and therapeutic target in prostate cancer.