C/EBPβ regulates homeostatic and oncogenic gastric cell proliferation

Regalo, Gonçalo; Förster, Susann; Resende, Carlos; Bauer, Bianca; Fleige, Barbara; Kemmner, Wolfgang; Schlag, Peter M.; Meyer, Thomas F.; Machado, José Carlos; Leutz, Achim

doi:10.1007/s00109-016-1447-7

Cited by 28 publications

(24 citation statements)

References 35 publications

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“…The identification and characterization of inhibitory compounds with this cell line has shown that candidate inhibitors affect MYB activity also indirectly by targeting the transcription factor C/EBPβ, a crucial co-operation partner required by MYB to induce MIM1 expression 28 – 31 . Although small-molecule inhibitors of C/EBPβ are also of interest given that C/EBPβ has pro-oncogenic roles in several tumors 32 – 36 , we wanted to be able to search for MYB inhibitors in a more focused manner. We therefore generated the reporter cell line illustrated schematically in Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

Yusenko

Jakobs

Klempnauer

2018

Sci Rep

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The transcription factor MYB plays key roles in hematopoietic cells and has been implicated the development of leukemia. MYB has therefore emerged as an attractive target for drug development. Recent work has suggested that targeting MYB by small-molecule inhibitors is feasible and that inhibition of MYB has potential as a therapeutic approach against acute myeloid leukemia. To facilitate the identification of small-molecule MYB inhibitors we have re-designed and improved a previously established cell-based screening assay and have employed it to screen a natural product library for potential inhibitors. Our work shows that teniposide and etoposide, chemotherapeutic agents causing DNA-damage by inhibiting topoisomerase II, potently inhibit MYB activity and induce degradation of MYB in AML cell lines. MYB inhibition is suppressed by caffeine, suggesting that MYB is inhibited indirectly via DNA-damage signalling. Importantly, ectopic expression of an activated version of MYB in pro-myelocytic NB4 cells diminished the anti-proliferative effects of teniposide, suggesting that podophyllotoxins disrupt the proliferation of leukemia cells not simply by inducing general DNA-damage but that their anti-proliferative effects are boosted by inhibition of MYB. Teniposide and etoposide therefore act like double-edged swords that might be particularly effective to inhibit tumor cells with deregulated MYB.

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Section: Resultsmentioning

confidence: 99%

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

Yusenko

Jakobs

Klempnauer

2018

Sci Rep

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“…CCAAT/enhancer-binding protein β (C/EBPβ) is a member of the basic leucine zipper (bZIP) class of transcription factors and is involved in regulating cell growth, differentiation, inflammation, metabolism, survival, and tumorigenesis [1,2,3,4,5]. The growth-regulatory function of C/EBPβ has been reported to inhibit [6,7] or promote [8,9,10,11] cell proliferation, both in normal [6,8,9,10] and cancer cells [7,9,11]. For example, in C/EBPβ knock-out mice, hyperproliferation of epidermal keratinocytes was observed [6], but cell proliferation of B lymphocytes and gastric mucosa was decreased [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…The growth-regulatory function of C/EBPβ has been reported to inhibit [6,7] or promote [8,9,10,11] cell proliferation, both in normal [6,8,9,10] and cancer cells [7,9,11]. For example, in C/EBPβ knock-out mice, hyperproliferation of epidermal keratinocytes was observed [6], but cell proliferation of B lymphocytes and gastric mucosa was decreased [8,9]. Thus, it is important to investigate how the function of C/EBPβ is determined in the cellular context and to determine what elicits these opposite growth responses including upstream regulators and downstream effectors.…”

Section: Introductionmentioning

confidence: 99%

C/EBPβ Is a Transcriptional Regulator of Wee1 at the G2/M Phase of the Cell Cycle

Lee

Sung

Choi

et al. 2019

Cells

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The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein were expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying the G2/M transition in the cell cycle. In C/EBPβ-knockdown cells, a prolonged increase in phosphorylation of cyclin dependent kinase 1 at tyrosine 15 (Y15-pCDK1) was displayed with simultaneously increased Wee1 and decreased Cdc25B expression. Chromatin immunoprecipitation (ChIP) analysis showed that C/EBPβ bound to distal promoter regions of WEE1 and repressed WEE1 transcription through its interaction with histone deacetylase 2. Treatment of C/EBPβ-knockdown cells with a Wee1 inhibitor induced a decrease in Y15-pCDK1 and recovered cells from G2/M arrest. In the xenograft tumors, the depletion of C/EBPβ significantly reduced tumor growth. Taken together, these results indicate that Wee1 is a novel transcription target of C/EBPβ that is required for the G2/M phase of cell cycle progression, ultimately regulating proliferation of NSCLC cells.

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“…C/EBPβ is overexpressed in human intestinal-type gastric cancers,26,27 human gastric cancer,28 ovarian cancer,29 colorectal cancer,30,31 etc. It promotes cell proliferation, invasion, migration and metastasis inhibits cell differentiation and apoptosis promotes inflammation, immune suppression, and pro-oncogenic functions 14,28,31–33. Overexpression of C/EBPβ promoted cell invasive and migratory activity; downregulation of C/EBPβ suppressed malignant activities of 786-O cells.…”

Section: Discussionmentioning

confidence: 99%

<p>TNIP1 Inhibits Proliferation And Promotes Apoptosis In Clear Cell Renal Carcinoma Through Targeting C/Ebpβ</p>

Yang¹,

Fan²,

Han³

et al. 2019

OTT

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Background/PurposeTNF-α-induced protein 3-interacting protein 1 (TNIP1) is active in various cancers, but its expression and function in renal cell carcinoma (RCC) have not been described. This study investigated the role of TNIP1 in clear cell renal cell carcinomas (ccRCC), which accounts for 75–80% of RCC and has a poor prognosis.MethodsThe expression of TNIP1 in human ccRCC tissues and cells was detected by real-time quantitative reverse transcription–polymerase chain reaction (qRT-PCR), Western blot (WB), and immunohistochemical (IHC) staining. Cell proliferation was assayed by a cell counting kit (CCK)-8 assay; cell cycle analysis and apoptosis assay were done by flow cytometry.ResultsTNIP1 is downregulated in both ccRCC human tissues and cells. Besides, TNIP1 downregulation promoted cell proliferation with more cell cycle entry, and inhibited apoptosis. TNIP1 downregulation was associated with increased of expression of the Bcl-2 anti-apoptosis gene and decreased expression of the Bax apoptosis-promoting gene and cleaved-caspase-3 by negatively regulating C/EBPβ expression.ConclusionTNIP1 acted as a tumor-inhibitor in ccRCC by targeting C/EBPβ. The results warrant study of TNIP1 as a potential diagnostic marker and therapeutic target of ccRCC.

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C/EBPβ regulates homeostatic and oncogenic gastric cell proliferation

Cited by 28 publications

References 35 publications

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

C/EBPβ Is a Transcriptional Regulator of Wee1 at the G2/M Phase of the Cell Cycle

<p>TNIP1 Inhibits Proliferation And Promotes Apoptosis In Clear Cell Renal Carcinoma Through Targeting C/Ebpβ</p>

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