Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms

Albero, Robert; Enjuanes, Anna; Demajo, Santiago; Castellano, Giancarlo; Pinyol, Magda; García, Noelia; Capdevila, Cristina; Clot, Guillem; Suárez-Cisneros, Helena; Shimada, Mei; Karube, Kennosuke; López‐Guerra, Mònica; Colomer, Dolors; Beà, Sı́lvia; Martin-Subero, José Ignacio; Campo, Elı́as; Jares, Pedro

doi:10.1172/jci96520

Cited by 33 publications

(32 citation statements)

References 58 publications

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“…The total RNA from Hela cells was extracted using TRIzol@ Reagent (Invitrogen, USA). Reverse transcription and qRT-PCR were performed as described previously [8, 17, 18]. Amplification and detection of specific products were performed with the ABI stepone plus (PE Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

et al. 2019

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Background Mitofusin 2 (Mfn2) is outer membrane protein, as the inhibitor of Ras protein. This study aimed to investigate the effect of Mfn2 on cell proliferation, and cell-cycle in Hela cervical carcinoma cell lines. Methods After treated with Adv-mfn2 or Adv-control for 48 h and 60 h, the RNA and protein of Mfn2 in Hela cells were detected by qRT-PCR and western blot. The immunofluorescence assay was performed to observe the expression and sub-location of Mfn2 in Hela cells. The flow cytometry was performed to detect the cell cycle of Hela cells, while western blots were performed to observe the Ras-NF-κB signal pathway. Then, the xenografted cervix carcinoma mouse model was used to confirm the effect of Mfn2 in Hela cells in vivo and the expression of Ras-NF-κB signaling pathway in vivo. Results In immunofluorescence detection, Mfn2 was located in cytoplasmic, not in the nucleus. In addition, Mfn2 inhibited cell proliferation of Hela cells through reducing PCNA protein expression. Mfn2 induced arrest in G0/G1 phase of the cell cycle in Hela cells. Meanwhile, Mfn2 reduced Cyclin D1 protein expression. Moreover, Mfn2 decreased the Ras signal pathway proteins such as Myc, NF-κB p65, STAT3 in a dose-dependent manner. Then, the in vivo experiment also confirmed that Mfn2 could inhibit the tumor growth, and depress the Cyclin D1, Ras, Myc, NF-κB p65, Erk1/2 and mTOR protein expression. Conclusions Mfn2 could significantly inhibit cell proliferation in Hela cells. It might be acted as an potential anti-cancer target through inducing cell cycle arrest in human cervical carcinoma cells.

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Section: Methodsmentioning

confidence: 99%

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

et al. 2019

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“…Cyclin D1, an abundant protein in the G1 phase of the cell cycle, can induce global transcriptional downregulation in lymphoid neoplasms [ 27 ], and also can be critical for proliferating cells in G1/S transition [ 28 , 29 ]. Deregulation of cyclin D1 has been reported to be observed in cancers including breast cancer and lung cancer cells [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

Exogenous C8-Ceramide Induces Apoptosis by Overproduction of ROS and the Switch of Superoxide Dismutases SOD1 to SOD2 in Human Lung Cancer Cells

Chang

Fong

Tsai

et al. 2018

IJMS

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Ceramides, abundant sphingolipids on the cell membrane, can act as signaling molecules to regulate cellular functions including cell viability. Exogenous ceramide has been shown to exert potent anti-proliferative effects against cancer cells, but little is known about how it affects reactive oxygen species (ROS) in lung cancer cells. In this study, we investigated the effect of N-octanoyl-D-erythro-sphingosine (C8-ceramide) on human non-small-cell lung cancer H1299 cells. Flow cytometry-based assays indicated that C8-ceramide increased the level of endogenous ROS in H1299 cells. Interestingly, the ratio of superoxide dismutases (SODs) SOD1 and SOD2 seem to be regulated by C8-ceramide treatment. Furthermore, the accumulation of cell cycle G1 phase and apoptotic populations in C8-ceramide-treated H1299 cells was observed. The results of the Western blot showed that C8-ceramide causes a dramatically increased protein level of cyclin D1, a critical regulator of cell cycle G1/S transition. These results suggest that C8-ceramide acts as a potent chemotherapeutic agent and may increase the endogenous ROS level by regulating the switch of SOD1 and SOD2, causing the anti-proliferation, and consequently triggering the apoptosis of NSCLC H1299 cells. Accordingly, our works may give a promising strategy for lung cancer treatment in the future.

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“…In fact, Notch3 overexpression increased the abundance of several interrelated and/or downstream molecules such as TAL1, c-Myb and Cyclin D1 (Figure 3C). Upon overexpression, c-Myb and Cyclin D1 deregulate cellular homeostasis and may act as proapoptotic factors (27, 28), providing an explanation of the failure of complete rescue from the drug effects in Notch3/TAL1 double-transfected cells. In patient-derived primary T-ALL cells, the reduction in viable cell numbers was mostly associated with the decreased expression of TAL1 and NOTCH3 under treatment with S2116 and S2157 (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

Eradication of Central Nervous System Leukemia of T-Cell Origin with a Brain-Permeable LSD1 Inhibitor

Saito

Kikuchi

Koyama

et al. 2019

Clinical Cancer Research

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Purpose: Lysine-specific demethylase 1 (LSD1) regulates several biological processes via the bifunctional modulation of enhancer functions. Recently, we reported that LSD1 overexpression is a founder abnormality of T-cell leukemogenesis and is maintained in fully transformed T-cell acute lymphoblastic leukemia (T-ALL) cells. On the basis of this finding, we attempted to develop novel LSD1 inhibitors effective for T-ALL with central nervous system (CNS) involvement. Experimental design: We chemically modified the prototype LSD inhibitor tranylcypromine (TCP) and screened for cytotoxicity against TCP-resistant T-ALL cell lines. In vivo efficacy of novel LSD1 inhibitors was examined in immunodeficient mice transplanted with luciferase-expressing T-ALL cell lines, which faithfully reproduce human T-ALL with CNS involvement. Results: We found robust cytotoxicity against T-ALL cells, but not normal bone marrow progenitors, for two N-alkylated TCP derivatives, S2116 and S2157. The two compounds induced apoptosis in TCP-resistant T-ALL cells in vitro and in vivo by repressing transcription of the NOTCH3 and TAL1 genes through increased H3K9 methylation and reciprocal H3K27 deacetylation at super-enhancer regions. Both S2116 and S2157 significantly retarded the growth of T-ALL cells in xenotransplanted mice and prolonged the survival of recipients as monotherapy and in combination with dexamethasone. Notably, S2157 could almost completely eradicate CNS leukemia because of its ability to efficiently pass through the blood-brain barrier. Conclusion: These findings provide a molecular basis and rationale for the inclusion of a brain-permeable LSD1 inhibitor, S2157, in treatment strategies for T-ALL with CNS involvement.

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Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms

Cited by 33 publications

References 58 publications

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

Exogenous C8-Ceramide Induces Apoptosis by Overproduction of ROS and the Switch of Superoxide Dismutases SOD1 to SOD2 in Human Lung Cancer Cells

Eradication of Central Nervous System Leukemia of T-Cell Origin with a Brain-Permeable LSD1 Inhibitor

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