Epigenetic modifications play important roles in regulating the self-renewal and differentiation of hematopoiesis. was suppressed by 4SC-202, while up-regulation of HO-1 significantly weakened the 4SC-202-induced suppression of the NF-B pathway, thereby attenuating the efficacy of 4SC-202. However, down-regulation of HO-1 enhanced the sensitivity of 4SC-202 against SKM-1 cells. Moreover, SKM-1 cells were transfected with HO-1 overexpression lentivirus, subsequently injected into the tail vein of NOD/SCID mice, followed by administration of 4SC-202 in mice. As a result, up-regulation HO-1 could partially attenuate 4SC-202-suppressed MDS cells growth in NOD/SCID mice. In conclusion, 4SC-202 could induce apoptosis via the NF-B pathway, and our present finding may provide a novel therapeutic strategy for MDS. strong class=”kwd-title” Keywords: 4SC-202, human histone lysine-specific demethylase 1 (LSD1), class I HDACs, heme oxygenase-1 (HO-1), myelodysplastic syndrome (MDS), NF-B pathway, apoptosis Introduction Myelodysplastic syndrome (MDS) is a clonal disease of pathological hematopoiesis, which can be easily transformation into acute myeloid leukemia (AML). MDS is mainly characterized by the presence of peripheral cytopenia, accumulation of primary cells, dysplastic hematopoietic differentiation, but lacks the characteristics of acute leukemia. Currently, conventional chemotherapy can relieve cytopenia, improve quality of life and delay disease development, however, MDS patients are threatened by poor prognosis in the case of chemotherapy resistance. Despite the long-term survival in 30%-40% MDS patients via allogeneic hematopoietic stem cell transplantation (allo-HSCT), most MDS patients are elderly and allo-HCST itself causes serious complications and mortality [1]. Therefore, it is urgently required to explore feasible therapeutic approaches in MDS in clinical practice. Epigenetic modifications play crucial roles in regulating the self-renewal and differentiation of hematopoiesis, which are also the main oncogenic cause of MDS and AML. Over the past decade, several epigenetic regulators have been developed and assessed in preclinical and clinical studies. In addition to hypomethylating agents in this category, inhibitor of the human histone lysine-specific demethylase 1 (LSD1) is considered as the most promising epigenetic approach ameliorating MDS and AML, which invokes the myeloid development programs [2-4]. The overexpression of LSD1 has Tin(IV) mesoporphyrin IX dichloride been reported in approximately 60% of MDS patients [2]. In a spectrum of LSD1 inhibitors combined with Rabbit polyclonal to ATF2 conventional chemotherapy agents, LSD1 inhibitors reactivate myeloid differentiation in AML and MDS cells that are not spontaneously susceptible to chemotherapy, but hardly affect normal hematopoietic stem cells Tin(IV) mesoporphyrin IX dichloride [5]. Moreover, LSD1 has been reported to block myeloid maturation and to promote malignant hematopoiesis and the development and reproduction of leukemia [6-8], which is an extremely safe strategy for regeneration of normal hematopoiesis stem cells. LSD1, also known as KDM1A, AOF2 or BHC110, is the first discovered histone demethylase and mainly acts on histone 3 lysine 4 methylation 1/2 (H3K4me1/2) and histone 3 Lysine 9 methylation (H3K9me1/2) [9]. H3K4 methylation is a hallmark of active transcription, while H3K4 demethylation acts as a transcriptional co-repressor [5]. Among them, H3K4me2 is a marker for both activity enhancer and promoter [10]. LSD1 is involved in different complexes to promote H3K4 demethylation and to form chromatin into an inhibitory conformation, such as a CoREST transcriptional repressor complex composed of LSD1 and histone deacetylase 1/2 (HDAC1/2). LSD1 is abnormally blind to super-suppressor gene. Silencing LSD1 activates GFI-1, which is Tin(IV) mesoporphyrin IX dichloride identified as the signature of LSD1 super-enhance activation, thereby hindering MDS and MDS-associated leukemia oncogenic programs [3,11]. GFI-1 can bind with histone deacetylases to trigger transcriptional repression and is associated with HDAC1/2/3. The signal that promotes LSD1 demethylation activity may be the regional deacetylation marker on histone H3 taken out with the LSD1 downstream gene HDAC1/2 [12-14]. HDAC gets rid of acetyl groupings from lysine in histones, repressing DNA transcription [15] thereby. Co-treatment of LSD1 antagonist and HDACs inhibitor could enhance the success of mice engrafted with individual AML cells considerably, without the toxicity [14]. Concentrating on the CoREST complicated with dual HDACs and LSD1 inhibitors can be effective by slowing tumor cell development within a melanoma mouse xenograft model [16]. As a result, we postulated that co-inhibition of LSD1 and HDACs would activate repressed genes synergistically, inducing apoptosis and leading to cell routine arrest in MDS cells thereby. 4SC-202.