Vol.:(0123456789) 1 3 Journal of Cancer Research and Clinical Oncology https://doi.org/10.1007/s00432-018-2733-2 ORIGINAL ARTICLE – CANCER RESEARCH Prognostic value of histone marks H3K27me3 and H3K9me3 and modifying enzymes EZH2, SETDB1 and LSD-1 in colorectal cancer Sónia Carvalho 1,2  · Micaela Freitas 2  · Luís Antunes 3  · Sara Monteiro‑Reis 2  · Marcia Vieira‑Coimbra 2  · Ana Tavares 1  · Sofa Paulino 1,2  · José Flávio Videira 4  · Carmen Jerónimo 2,5  · Rui Henrique 1,2,5 Received: 28 May 2018 / Accepted: 4 August 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Purpose Studies on the performance of epigenetic-based biomarkers in colorectal cancer (CRC) are scarce and have shown contradictory results. Thus, we sought to examine the prognostic value of histone-modifying enzymes (EZH2, SETDB1 and LSD-1) and histone post-translational marks (H3K27me3 and H3K9me3) in CRC. Methods A retrospective series of 207 CRC patients primarily submitted to surgery in a cancer center was included in this study. Clinicopathological data were retrieved. One representative parafn block per case was selected for immunohisto- chemistry, including normal and CRC tissues whenever possible. The percentage of positive nuclear staining (digital image analysis) was used to classify patients into “low” and “high” expression groups for each biomarker. Correlations between immunoexpression levels, clinicopathological features and clinical outcomes [disease-specifc (DSS) and disease-free (DFS) survival] were examined. Statistical signifcance was set at p < 0.05. Results CRC tissues showed signifcantly lower expression of SETDB1 and higher expression of the remainder four bio- markers compared to normal mucosa. High EZH2 expression correlated with disease recurrence/progression, whereas low LSD1 expression and high H3K9me3 and H3K27me3 expression were associated with more advanced stage. In multivariable analysis, cases with high LSD1 expression displayed signifcantly better DSS and DFS (HR 0.477, 95% confdence interval: 0.247–0.923) adjusted for pathological TNM stage. Conclusion EZH2, SETDB1, LSD1, H3K9me3 and H3K27me3 expression are altered in CRC and may play a role in colorectal carcinogenesis. LSD1 immunoexpression levels independently predicted patient outcome in this cohort. Further investigations, using larger series, are warranted to confrm its potential clinical value and unravel underlying molecular mechanisms. Keywords Colorectal cancer · Epigenetics · Histone modifcations · Prognosis · Biomarkers Abbreviations CI Confdence interval CRC Colorectal cancer Carmen Jerónimo and Rui Henrique jointly served as senior authors * Rui Henrique rmhenrique@icbas.up.pt; henrique@ipoporto.min-saude.pt 1 Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal 2 Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal 3 Department of Epidemiology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal 4 Department of Surgical Oncology and Clinics of Digestive Tract Cancer, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal 5 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal