Csig-20. Rbbp4/p300 Complex Controls Genes Involved in Unfolded Protein Response Signaling and Is a Potential Target for Enhancing Glioblastoma Vulnerability to Endoplasmic Reticulum Stressors
Year: 2025
Type: conference-abstract
Abstract: The unfolded or misfolded proteins lead to endoplasmic reticulum stress (ER-stress), which activates the unfolded protein response (UPR) through IRE1, PERK, and ATF6 downstream pathways to enhance the survival, proliferation, and development of therapy resistance in glioblastoma cells. We previously demonstrated that the RBBP4/p300 complex regulates transcription of genes critical for glioblastoma (GBM) aggressiveness and response to therapy. However, the role of this complex in regulating UPR genes remains unclear. Therefore, we used RNA- and ChIP-sequencing to identify whether UPR genes are regulated by the RBBP4/p300 complex in patient-derived GBM43 cells. Our data show that silencing RBBP4 or p300 by shRNA suppresses the expression of key UPR genes, including XBP1, PPP1R15A, ERN1, ATF4, DDIT3, and ATF6. ChIP-sequencing confirmed the co-occupancy of RBBP4 and p300 proteins within promoters or enhancers of the UPR genes regulated by the RBBP4/p300 complex. Moreover, silencing either RBBP4 or p300 diminished the decoration of the promoters/enhancers of RBBP4/p300 target UPR genes by the acetylated lysine 27 of histone H3 (H3K27ac). Interestingly, tunicamycin induced ER-stress and activated UPR signaling in GBM43 cells expressing the control shRNA (shNT) but not in the shRBBP4 expressing cells, as evidenced by the increased spliced XBP1 variant, CHOP, and phosphorylation of serine 51 of ELF2α (ELF2αS51). In addition, tunicamycin increased the expression of cleaved-PARP in the control shNT cells but not in the shRBBP4 expressing cells, suggesting that disrupting RBBP4/p300 complex enhances vulnerability to ER-stress in GBM cells. Finally, the expression of UPR genes directly correlated with RBBP4 and p300 expression in GBM patient specimens. In conclusion, these findings suggest that the RBBP4/p300 complex plays a role in regulating ER-stress-induced UPR signaling by controlling the UPR genes. Further studies are required to establish the impact of disrupting this complex on sensitivity to ER-stress-inducing drugs, including inhibitors of protein deubiquitylation.
Source: Neuro-Oncology
Authors: Josephine Mapunda, Gaspar Kitange
Institution: University of Minnesota
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416141471
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