High nuclear expression levels of histone-modifying enzymes LSD1, HDAC2 and SIRT1 in tumor cells correlate with decreased survival and increased relapse in breast cancer patients

Abstract

BackgroundBreast cancer is a heterogeneous disease with a highly variable clinical outcome in which both genetic and epigenetic changes have critical roles. We investigated tumor expression levels of histone-modifying enzymes LSD1, HDAC2 and SIRT1 in relation with patient survival and tumor relapse in a retrospective cohort of 460 breast cancer patients. Additionally, we correlated expression levels with tumor differentiation and tumor cell proliferation.MethodsImmunohistochemical staining for LSD1, HDAC2 and SIRT1 was performed on tissue microarrays of tumor and corresponding normal formalin-fixed paraffin-embedded tissues from breast cancer patients. Median nuclear expression levels in tumor tissues were used to divide the patients into low and high expression categories. In combined expression analyses, patients were divided into four subgroups: 1, all enzymes below-median; 2, one enzyme above-median; 3, two enzymes above-median; 4, all three enzymes above-median. The Cox proportional hazard model was used for univariate and multivariate survival analyses. The Pearson Chi-square method was used to assess correlation of combined expression levels with tumor cell proliferation and tumor differentiation.ResultsExpression of LSD1 and SIRT1, but not of HDAC2, was significantly increased in tumor tissues compared to their normal counterparts (both p < 0.001). Multivariate survival analyses identified SIRT1 as independent prognostic factor for relapse-free survival (RFS) with a hazard ratio (HR) of 1.34 (95% CI = 1.04-1.74, p = 0.02). For overall survival (OS), no significant differences were found when the individual enzymes were analyzed. Analyses of combined expression levels of the three histone-modifying enzymes correlated with OS (p = 0.03) and RFS (p = 0.006) with a HR of respectively 1.49 (95% CI = 1.07-2.08) and 1.68 (95% CI = 1.16-2.44) in multivariate analyses and were also related to tumor differentiation (p < 0.001) and tumor cell proliferation (p = 0.002).ConclusionsWhen the combined expression levels were analyzed, high expression of LSD1, HDAC2 and SIRT1 showed shorter patient survival time and shorter time to tumor relapse and correlated with poor tumor differentiation and a high level of tumor cell proliferation. Expression of these histone-modifying enzymes might therefore be involved in breast cancer pathogenesis.

HDAC2 overexpression is a poor prognostic factor of breast cancer patients with increased multidrug resistance-associated protein expression who received anthracyclines therapy

“…These findings suggested that HDAC2 may be involved in the malignancy of breast cancer. Many reports have correlated HDAC2 expression with poor clinical outcome in patients with breast cancer (21,32). However, our data do not fully agree with previous studies.…”

Integrated genomic analyses identify KDM1A's role in cell proliferation via modulating E2F signaling activity and associate with poor clinical outcome in oral cancer

“…KDM1A expression was also identified as an independent prognosticator of a few cancers. It has been reported that elevated expression of KDM1A is associated with poor prognosis in cancers [24,26,54,55]. Our data also identified the prognostic role of KDM1A in two independent cohorts of oral cancer.…”

Synthesis and biological evaluation of novel (E)-N′-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors

“…All the 9 tumor cell lines were picked up from diversity cancers and all of the cells had been demonstrated to bear a high expression level of LSD1. 15,17,18 As shown in Table 4, compounds 5a and 5n treatment resulted in significantly cell viability inhibition with the IC 50 values ranging from 200nM to 3µM. Among these cancer cell lines, A549, H1299, A2780, HCT116, MCF-7，MDA-MB-231 and DU145 were sensitive to compound 5a with IC 50 < 1 µM and A549，H1299, A2780, HCT116，MCF-7, MDA-MB-231, PC-3 and DU145 were sensitive to compound 5n with IC 50 < 1 µM.…”