LncRNA HOTAIR regulates the expression of E-cadherin to affect nasopharyngeal carcinoma progression by recruiting histone methylase EZH2 to mediate H3K27 trimethylation.

There has been increasing evidence for the function of long non-coding RNA (lncRNA) in nasopharyngeal carcinoma (NPC). We aim to delve into the position of lncRNA HOX antisense intergenic RNA (HOTAIR), together with enhancer of zeste homolog 2 (EZH2), E-cadherin and trimethylation of lysine 27 on histone H3 (H3K27me3) in NPC. HOTAIR, EZH2, and E-cadherin expression in NPC tissues and cells were tested. NPC cell biological functions were examined through gain-of and loss-of function assays. The mechanism of lncRNA HOTAIR/E-cadherin/EZH2/H3K27 axis in NPC was decoded. LncRNA HOTAIR and EZH2 were highly expressed in NPC, and E-cadherin was lowly expressed. Down-regulation of HOTAIR or EZH2 inhibited NPC cell progression and tumor growth. HOTAIR recruited histone methylase EZH2 to mediate trimethylation of H3K27 and regulated E-cadherin expression. HOTAIR inhibits E-cadherin by stimulating the trimethylation of H3K27 to promote NPC cell progression through recruiting histone methylase EZH2.

Yang FL ，Wei YX ，Liao BY ，Wei GJ ，Qin HM ，Pang XX ，Wang JL ... -  《-》

Ropivacaine suppresses the progression of renal cell carcinoma through regulating the lncRNA RMRP/EZH2/CCDC65 axis.

Renal cell carcinoma (RCC) is a common malignancy. Local anesthetics were displayed powerful effects against various cancers. This study aims to probe the functions and molecular mechanism of ropivacaine in RCC. Different concentrations of ropivacaine were performed to administrate RCC cells including 786-O and Caki-1 cells. Cell viability and cell apoptosis were examined using CCK-8 and flow cytometry, respectively. Cell migration and invasion were determined by transwell assay. RMRP and CCDC65 expression was firstly predicted using TCGA dataset and further validated in RCC cells using qRT-PCR and western blot. The interactions among RMRP, EZH2 and CCDC65 were verified by RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays. Ropivacaine effectively suppressed RCC cell viability, migration and invasion and enhanced cell apoptosis rate. Aberrantly elevated RMRP expression in RCC tissues was predicted by TCGA database. Interestingly, overexpressed RMRP observed in RCC cells could be also blocked upon the administration of ropivacaine. Likewise, RMRP knockdown further strengthened ropivacaine-mediated tumor suppressive effects on RCC cells. In terms of mechanism, RMRP directly interacted with EZH2, thereby modulating the histone methylation of CCDC65 to silence its expression. Moreover, ropivacaine inhibited tumor growth in mice bearing RCC tumor through regulating RMRP/EZH2/CCDC65 axis. In sum up, our work revealed that ropivacaine suppressed capacities of RCC cell viability, migration and invasion through modulating the RMRP/EZH2/CCDC65 axis, which laid the experimental foundation of ropivacaine for clinical application in the future.

Xiong Y ，Zheng X ，Deng H 《DARU-Journal of Pharmaceutical Sciences》

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and enhancer of Zeste homolog 2 in breast cancer both in vitro and in vivo.

Histone methyltransferases are enzymes that selectively methylate lysine or arginine residues on both histone and non-histone proteins, categorized into lysine methyltransferases and arginine methyltransferases. Notably, EZH2 and PRMT5 are known for catalyzing trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3, respectively. These methylation events are recognized as characteristic histone-repressive marks in cancer. The over expression of PRMT5 and EZH2 were reported in various cancers and recognized as a drug target. The study aims to explore the inhibitory potential of phytocompound, Epigallocatechin-3-gallate (EGCG), against PRMT5 and EZH2 in the breast cancer model. Screening of an array of phytocompounds was conducted through a combination of in-silico and in-vitro assays. Interactions between EGCG and human PRMT5: MEP50 and EZH2 were evaluated using molecular docking. Binding efficiency was validated, by Surface Plasmon Resonance studies and inhibitory potential was accessed by in vitro methylation followed by western blots, ELISA, and cell-based assays. In-vivo efficacy of EGCG was carried on cell line derived mice xenograft model. EGCG demonstrated robust interactions with PRMT5:MEP50 complex and EZH2, particularly within the SAM binding site. Surface Plasmon Resonance analysis revealed strong binding affinity in nanomolar concentrations, particularly with PRMT5-MEP50 compared to EZH2. In-vitro assays confirmed EGCG's ability to inhibit PRMT5 and EZH2, leading to a decrease in their catalytic products, namely H4R3me2s and H3K27me3, respectively. EGCG treatment induced both autophagy and apoptosis invitro. In-vivo studies demonstrated significant reductions in tumor size and the proliferation marker ki67, accompanied by a decrease in histone repressive marks. The findings suggest that EGCG effectively inhibits PRMT5 and EZH2, underscoring its potential for combined therapeutic strategies in cancer treatment.

Nalla K ，Chatterjee B ，Poyya J ，Swain A ，Ghosh K ，Pan A ，Joshi CG ，Manavathi B ，Kanade SR ... -  《-》

HNRNPH1 stabilizes FLOT2 mRNA in a non-canonical m6A-dependent manner to promote malignant progression in nasopharyngeal carcinoma.

The mechanism underlying the upregulation of FLOT2 in tumors, especially its regulatory mechanism at the RNA level, remains unclear. The purpose of this study is to investigate the regulatory mechanism of FLOT2 upregulation in tumors, particularly at the RNA level, and its role in nasopharyngeal carcinoma (NPC) progression. We identified the role of HNRNPH1 in maintaining FLOT2 mRNA stability and its dependency on the m6A modification. We explored the interaction between HNRNPH1 and METTL14, a key enzyme in m6A modification, and its impact on FLOT2 mRNA stability. We also assessed the expression levels of HNRNPH1 and METTL14 in NPC and their correlation with patient malignancy and prognosis. Experimental approaches included in vitro and in vivo assays to study the effects of HNRNPH1 knockdown on NPC cell proliferation and invasion. HNRNPH1 is highly expressed in NPC and stabilizes FLOT2 mRNA through an m6A-dependent mechanism. HNRNPH1 interacts with METTL14 to prevent its degradation by STUB1 E3 ligases, leading to increased m6A modification of FLOT2 by METTL14. Additionally, IGF2BP3 was shown to recognize the m6A modification on FLOT2 mRNA, further stabilizing it. High expression of HNRNPH1 and METTL14 were observed in NPC and were positively associated with increased malignancy and poorer patient outcomes. HNRNPH1 knockdown significantly reduced the proliferation and invasive capabilities of NPC cells. Restoration of METTL14 in HNRNPH1-depleted cells could rescue FLOT2 expression and the malignant phenotype, but this effect was negated by the knockdown of FLOT2. Our study elucidates a novel mechanism where HNRNPH1 and METTL14 work together to maintain the stability of FLOT2 mRNA, thereby promoting NPC progression. Targeting this pathway presents a promising therapeutic strategy for the treatment of NPC.

Li Q ，Liu J ，Zeng C ，Qin D ，Zhang Z ，Lv Q ，Li J ，Huang W ... -  《-》

lncRNA GHET1 regulates extravillous trophoblastic phenotype via EZH2/LSD1-mediated MT2A epigenetic suppression in pre-eclampsia.

Wan P ，Huang J ，Liu W ，Su X ，Zhao B ，Wang X ，Zhao L ... -  《-》