Transcription factor E2F3a regulates CASP8AP2 transcription and enhances sensitivity to chemotherapeutic drugs in acute lymphoblastic leukemia

Liu, Feifei; Wang, Kai-Ling; Deng, Liping; Liu, Xiao; Wu, Min-Yuan; Wang, Tianyou; Cui, Lei; Li, Zhigang

doi:10.1186/s12935-018-0531-1

Cited by 7 publications

(17 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The E2F transcription factor family serves a key role in cell cycle regulation ( 12 ). Our previous study reported that overexpression of E2F3a enhances the sensitivity of 697 and Reh cells to DNR ( 15 ). In the present study, immunofluorescence confocal microscopy analysis demonstrated that CREBBP and E2F3a co-localized in the nuclei of Jurkat and Reh cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study revealed that E2F3a activates the transcription of CASP8AP2 ( 15 ). Since CREBBP was indicated to interact with E2F3a, the role of CREBBP in the regulation of CASP8AP2 expression in leukemia cells was further investigated.…”

Section: Resultsmentioning

confidence: 99%

“…E2F3a is only expressed at the G 1 /S boundary ( 33 ), while E2F3b is expressed throughout the cell cycle and is associated with retinoblastoma protein (Rb) and Rb-associated proteins in a growth-arrested G 0 state ( 34 ). A previous study reported that low E2F3a expression was associated with adverse outcomes in pediatric patients with ALL, and overexpression of E2F3a may enhance the sensitivity to DNR, which increased the proportion of leukemia cells in the S and G 2 /M phases and accelerated cell proliferation ( 15 ). These findings are consistent with the biological manifestations of altered CREBBP expression as demonstrated in the present study, which suggested that CREBBP may influence E2F3a expression in leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that CASP8AP2 is a target gene of E2F3a, and low CASP8AP2 expression is associated with an unfavorable prognosis of pediatric patients with ALL ( 15 , 35 ). Furthermore, CASP8AP2 is a key protein involved in cell proliferation and S phase progression ( 36 , 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…Gene microarray analyses have detected E2F3 mRNA expression in diagnostic samples of ALL, while other members are low or undetectable ( 13 , 14 ). Furthermore, a previous study reported that overexpression of E2F3a in 697 and Reh cells accelerated cell proliferation, promoted leukemia cells to S and G 2 /M phases and enhanced sensitivity to chemotherapeutic drugs ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Downregulating CREBBP inhibits proliferation and cell cycle progression and induces daunorubicin resistance in leukemia cells

Gao

Liu

et al. 2020

Mol Med Rep

View full text Add to dashboard Cite

Low expression levels of CREB-binding protein (CREBBP) have been demonstrated to be associated with high minimal residual disease at the end of induction therapy and adverse long-term outcomes in pediatric patients with acute lymphoblastic leukemia (ALL). However, the effect of low CREBBP expression on the prognosis of ALL has not yet been investigated. In the present study, CREBBP was downregulated and overexpressed in ALL cell lines (Jurkat and Reh). Sensitivity to chemotherapy and cell proliferation activity was determined via a Cell Counting Kit-8 assay. Cell cycle analysis was performed using flow cytometry. Immunofluorescence confocal microscopy and co-immunoprecipitation (Co-IP) assays were performed to determine the interaction between CREBBP and E2F transcription factor 3a (E2F3a). The binding of CREBBP to downstream gene caspase 8 associated protein 2 (CASP8AP2) promoters was assessed using a chromatin immunoprecipitation assay, and mRNA expression levels were detected via reverse transcription-quantitative PCR. Western blot analysis was performed to detect protein expression of CREBBP, E2F3a and CASP8AP2. Downregulation of CREBBP increased the IC 50 value of daunorubicin; however, no significant affects were observed on the IC 50 values of vincristine and L-asparaginase. Furthermore, downregulation of CREBBP notably inhibited leukemia cell proliferation, accumulated cells in the G 0 /G 1 phase and decreased cell proportions in the S and G 2 /M phases. Co-IP analysis demonstrated that CREBBP interacted with E2F3a, a transcription factor involved in G 1 /S transition. Immunofluorescence confocal microscopy indicated co-localization of CREBBP and E2F3a at the cell nucleus. Furthermore, E2F3a protein expression decreased in CREBBP RNA interference treated Jurkat and Reh cells. CASP8AP2, a target gene of E2F3a, was also identified to be a downstream gene of CREBBP. In addition, decreased IC 50 value and cell proportions in the G 0 /G 1 phase, accelerated cell proliferation and upregulated E2F3a and CASP8AP2 expression were exhibited in CREBBP overexpressed cells. Taken together, the results of the present study suggested that CREBBP downregulation affects proliferation and cell cycle progression in leukemia cells, potentially via the interaction and regulation of E2F3a, resulting in chemotherapy resistance. Thus, targeting CREBBP may be a therapeutic strategy for treating pediatric patients with ALL.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%