作者: Johnson, Jessica D. ; Venkata, Prabhakar P. ; Sareddy, Gangadhara R. ; He, Yi ; Alejo, Salvador ; Viswanadhapalli, Suryavathi ; Chen, Yihong ; Zou, Yi ; Jayamohan, Sridharan ; Kost, Edward ; Vadlamudi, Ratna K. ; Lai, Zhao ; Jamwal, Diksha

Abstract:

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum‐based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy‐resistant disease. Recent studies have revealed that the epigenetic modifier lysine‐specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient‐derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin‐resistant A2780‐CP70 cells to carboplatin treatment and paclitaxel‐resistant SKOV3‐TR cells to paclitaxel. RNA‐seq analysis revealed that a combination of KDM1A‐KD and cisplatin treatment resulted in the downregulation of genes related to epithelial‐mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF‐κB pathway genes, and KDM1A‐KD or KDM1A inhibition reversed this effect. Importantly, KDM1A‐KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

2020-03-01·Leukemia1区 · 医学

LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia

1区 · 医学

Article

作者: Takaori-Kondo, Akifumi ; Kawahara, Masahiro ; Yamamoto, Ryusuke ; Tatsumi, Goichi ; Suzuki, Takayoshi ; Andoh, Akira ; Hishizawa, Masakatsu ; Kito, Katsuyuki

Super-enhancers (SEs) consist of enhancer clusters with abundant binding of transcription factors (TFs) and cofactors. LSD1 is a histone modifier that eliminates SE activity. However, whether SE suppression by LSD1 is associated with leukemogenesis remains unknown. In erythro-megakaryocyte lineage leukemia cells, activation of the SE of GFI1 (GFI1-SE) is related to induction of myeloid differentiation by LSD1 inhibitors NCD38 and NCD25 and to their antileukemia effect. Although functional TF-motifs were concentrated in an evolutionally conserved area, NCD38 barely induced additional TF recruitment. Instead, the transcription cofactors including LSD1, CoREST, HDAC1, and HDAC2 were evicted from GFI1-SE. Deletion of GFI1-SE impaired induction of myeloid differentiation by NCD38 and NCD25 in erythroleukemia cells. Gene set enrichment analysis revealed that the GFI1-SE deletion impaired NCD38-induced programs related to granulocyte differentiation and the CEBPA network, but restored NCD38-suppressed programs related to erythroid development, GATA1 targets, and acute myeloid leukemia (AML) clusters including FAB subtype M6 and AML with myelodysplastic syndrome-related chromosomal abnormalities. Ontologies of genes whose expression changes by NCD38 were canceled due to the GFI1-SE deletion showed enrichment in AML and neutropenia signatures. Collectively, our data suggest that sustainable repression of GFI1-SE by LSD1 is essential for sustenance of erythroleukemia cells.

2018-06-29·Oncotarget

Region-specific alteration of histone modification by LSD1 inhibitor conjugated with pyrrole-imidazole polyamide

Article

作者: Fukuyo, Masaki ; Yoda, Natsumi ; Kita, Kazuko ; Sato, Hiroaki ; Kaneda, Atsushi ; Okabe, Atsushi ; Nemoto, Tetsuhiro ; Takayanagi, Shihori ; Shiga, Naoki ; Shinohara, Ken-Ichi ; Sugiura, Masahiro ; Qin, Rui ; Suzuki, Takayoshi ; Alagarswamy, Kokiladevi ; Rahmutulla, Bahityar

Epigenome regulates gene expression to determine cell fate, and accumulation of epigenomic aberrations leads to diseases, including cancer. NCD38 inhibits lysine-specific demethylase-1 (LSD1), a histone demethylase targeting H3K4me1 and H3K4me2, but not H3K4me3. In this study, we conjugated NCD38 with a potent small molecule called pyrrole (Py) imidazole (Im) polyamide, to analyze whether targets of the inhibitor could be regulated in a sequence-specific manner. We synthesized two conjugates using β-Ala (β) as a linker, i.e., NCD38-β-β-Py-Py-Py-Py (NCD38-β₂P₄) recognizing WWWWWW sequence, and NCD38-β-β-Py-Im-Py-Py (NCD38-β₂PIPP) recognizing WWCGWW sequence. When RKO cells were treated with NCD38, H3K4me2 levels increased in 103 regions with significant activation of nearby genes (P = 0.03), whereas H3K4me3 levels were not obviously increased. H3K27ac levels were also increased in 458 regions with significant activation of nearby genes (P = 3 × 10^-10), and these activated regions frequently included GC-rich sequences, but less frequently included AT-rich sequences (P < 1 × 10^-15) or WWCGWW sequences (P = 2 × 10^-13). When treated with NCD38-β₂P₄, 234 regions showed increased H3K27ac levels with significant activation of nearby genes (P = 2 × 10^-11), including significantly fewer GC-rich sequences (P < 1 × 10^-15) and significantly more AT-rich sequences (P < 1 × 10^-15) compared with NCD38 treatment. When treated with NCD38-β₂PIPP, 82 regions showed increased H3K27ac levels, including significantly fewer GC-rich sequences (P = 1 × 10^-11) and fewer AT-rich sequences (P = 0.005), but significantly more WWCGWW sequences (P = 0.0001) compared with NCD38 treatment. These indicated that target regions of epigenomic inhibitors could be modified in a sequence-specific manner and that conjugation of Py-Im polyamides may be useful for this purpose.

100 项与 NCD38 相关的药物交易

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