Study on epigenetic regulatory mechanism of MBD4 with a germline loss-of-function mutation (rs140693) responsible for retinoblastoma chemoresistance via the cell cycle and apoptotic pathways.
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75% confidenceThe study investigates the epigenetic regulatory mechanism of MBD4 with a germline loss-of-function mutation (rs140693) responsible for retinoblastoma chemoresistance. MBD4 downregulation impairs carboplatin or etoposide efficacy in vitro and in vivo. The mutation affects the transcription and expression of downstream genes via epigenetic regulation.
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Abstract
Recurrence of high-risk advanced retinoblastoma (RB) is still a major obstacle even after enucleation due to resistance to adjuvant chemotherapy, especially in China. To identify any germline alterations or candidate genes associated with RB prognosis, we obtained whole-exome sequencing (WES) and reduced-representation bisulfite sequencing (RRBS) profiles by using patient peripheral blood samples, followed by clinical validation and functional characterization. For follow-up studies, we selected 17 candidate genes from the WES and RRBS analyses. Among them, MBD4, which carries a germline loss-of-function mutation (rs140693), was identified for further clinical replication. MBD4 downregulation significantly impaired carboplatin or etoposide efficacy in vitro and in vivo, respectively. There were marked decreases in the expression of 5 related genes plus increased DNA methylation in their promoters in Y79 (MBD4 -/- ) cells, along with even more significant effects after carboplatin treatment. MBD4 affected the transcription and expression of its downstream genes, such as FADD and P21, via MBDCap-PCR, ChIPqPCR, and reporter gene assays. Moreover, the germline mutation was responsible for MBD4 instability with attenuated binding to USP7, thereby leading to impaired drug sensitivity. It was confirmed by the reinstated susceptibility of Y79 (MBD4 -/- ) cells after MBD4-WT was restored. In the present study, our findings indicate that depletion or mutation of MBD4 interferes with the activation of the cell cycle and apoptosis via epigenetic regulation, thereby reducing drug susceptibility. It provides new insights into the role in RB chemoresistance of MBD4 as an epigenetic regulator, which might fuel the development of new RB-targeted strategies.