BRDT is a novel regulator of eIF4EBP1 in renal cell carcinoma

Abstract

Among all types of kidney diseases, renal cell carcinoma (RCC) has the highest mortality, recurrence and metastasis rates, which results in high numbers of tumor-associated mortalities in China. Identifying a novel therapeutic target has attracted increasing attention. Bromodomain and extraterminal domain (BET) proteins have the ability to read the epigenome, leading to regulation of gene transcription. As an important member of the BET family, bromodomain testis-specific protein (BRDT) has been well studied; however, the mechanism underlying BRDT in the regulation of RCC has not been fully investigated. Eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1) is a binding partner of eIF4E that is involved in affecting the progression of various cancer types via regulating gene transcription. To identify novel regulators of eIF4EBP1, an immunoprecipitation assay and mass spectrometry analysis was performed in RCC cells. It was revealed that eIF4EBP1 interacted with BRDT, a novel interacting protein. In addition, the present study further demonstrated that BRDT inhibitors PLX51107 and INCB054329 blocked the progression of RCC cells, along with suppressing eIF4EBP1 and c-myc expression. Small interfering (si) RNAs were used to knock down BRDT expression, which suppressed RCC cell proliferation and eIF4EBP1 protein expression. In addition, overexpression of eIF4EBP1 partially abolished the inhibited growth function of PLX51107 but knocking down eIF4EBP1 improved the inhibitory effects of PLX51107. Furthermore, treatment with PLX51107 or knockdown of BRDT expression decreased c-myc expression at both the mRNA and protein levels, and attenuated its promoter activity, as determined by luciferase reporter assays. PLX51107 also significantly altered the interaction between the c-myc promoter with eIF4EBP1 and significantly attenuated the increase of RCC tumors, accompanied by decreased c-myc mRNA and protein levels in vivo . Taken together, these data suggested that blocking of BRDT by PLX51107, INCB054329 or BRDT knockdown suppressed the growth of RCC via decreasing eIF4EBP1, thereby leading to decreased c-myc transcription levels. Considering the regulatory function of BET proteins in gene transcription, the present study suggested that there is a novel mechanism underlying eIF4EBP1 regulation by BRDT, and subsequently decreased c-myc in RCC, and further identified a new approach by regulating eIF4EBP1 or c-myc for enhancing BRDT-targeting RCC therapy.

Identification of Novel CircRNA-miRNA-mRNA Regulatory Network and Its Prognostic Prediction in Breast Cancer

“…In brief, EIF4EBP1 was found to be highly expressed, and the remaining four DEGs, including DUSP1, EGR2, EZH1, and CBX7, were displayed in low expression in BC patients. In the research of renal cell carcinoma, Wan et al suggested that EIF4EBP1 expressions were decreased by the regulation of bromodomain testis- Evidence-Based Complementary and Alternative Medicine specific protein, with the result of attenuating the increase of tumors [31]. hsa-miR-125b-5p is a miRNA that has already become a biomarker for cancer diagnosis, treatment, and prognosis [32].…”

The Functions of BET Proteins in Gene Transcription of Biology and Diseases

“…BRD2 and BRD4 occupy Nodal gene regulatory elements (NREs), and BRD4 downregulation facilitates exit and drives enhanced BRD2 NRE occupancy to promote differentiative Nodal-Smad2 signaling (Fernandez-Alonso et al, 2017). Finally, the aberrant expression of BRDT in esophageal carcinoma (Wang et al, 2021b), ovarian cancer (Chen, 2020), and renal cell carcinoma (Wan et al, 2020) also contributes to the context-dependent function of BET proteins and is an attractive target for selective inhibition, in particular for different cancer types.…”

Construction and Validation of a Prognostic Risk Model for Triple Negative Breast Cancer Based on Autophagy-Related Genes

“…Luosheng Zhang et al also found that CTSL involved in proliferation and invasion of ovarian cancer cells [22]. Some studies indicated EIF4EBP1 is involved in affecting the progression of various cancer types (including renal cell carcinoma, breast cancer) based on regulating gene transcription [23,24]. Kevin Luftman et al con rmed that silencing of VAMP3 could inhibit cancer metastasis [25].…”