Chromatin remodeling protein HELLS is critical for retinoblastoma tumor initiation and progression

Abstract

Retinoblastoma is an aggressive childhood cancer of the developing retina that initiates by biallelic RB1 gene inactivation. Tumor progression in retinoblastoma is driven by epigenetics, as retinoblastoma genomes are stable, but the mechanism(s) that drive these epigenetic changes remain unknown. Lymphoid-specific helicase (HELLS) protein is an epigenetic modifier directly regulated by the RB/E2F pathway. In this study, we used novel genetically engineered mouse models to investigate the role of HELLS during retinal development and tumorigenesis. Our results indicate that Hells-null retinal progenitor cells divide, undergo cell-fate specification, and give rise to fully laminated retinae with minor bipolar cells defects, but normal retinal function. Despite the apparent nonessential role of HELLS in retinal development, failure to transcriptionally repress Hells during retinal terminal differentiation due to retinoblastoma (RB) family loss significantly contributes to retinal tumorigenesis. Loss of HELLS drastically reduced ectopic division of differentiating cells in Rb1/p107-null retinae, significantly decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Despite its role in heterochromatin formation, we found no evidence that Hells loss directly affected chromatin accessibility in the retina but functioned as transcriptional co-activator of E2F3, decreasing expression of cell cycle genes. We propose that HELLS is a critical downstream mediator of E2F-dependent ectopic proliferation in RB-null retinae. Together with the nontoxic effect of HELLS loss in the developing retina, our results suggest that HELLS and its downstream pathways could serve as potential therapeutic targets for retinoblastoma.

The DNA-helicase HELLS drives ALK− ALCL proliferation by the transcriptional control of a cytokinesis-related program

“…In cancer, HELLS is deregulated in several settings i.e. gliomas 54 , retinoblastoma 55 , 56 , prostate 28 , breast carcinomas 57 , 58 , medulloblastoma 59 , leukemia 60 where it promotes cellular proliferation and stemness. A significant part of HELLS activity in these processes is mediated by its transcriptional function.…”

“…The way through which HELLS controls gene expression is still partially undefined. Its interaction with epigenetic silencers including G9a 61 and DNMTs 62 as well as with transcriptional factors like E2F3 28 , 56 and c-Myc 54 has been described. Here, we added an additional part of information showing that in the specific context of ALK − ALCL, HELLS interacts and functionally cooperates with the transcription factor YY1.…”

Retinoblastoma Tumor Suppressor Protein Roles in Epigenetic Regulation

“…DNA methylation is catalyzed by enzymes in the DNA methyltransferase family (DNMTs), including DNMT1, which is associated with the maintenance of DNA methylation [ 82 , 83 ], and DNMT3A and DNMT3B, which are responsible for de novo DNA methylation [ 84 ]. pRB not only transcriptionally represses the expression of DNMT1 and DNMT3A / B [ 85 , 86 , 87 ], but also physically interacts with DNMT1 and chromatin remodelers that can recruit DNMT1 and DNMT3A/B to affect DNA methylation [ 88 , 89 , 90 , 91 ].…”

“…In the HELLS-mediated transcriptional repression, HELLS also acts as a recruiting factor for DNMT1 and HDACs to establish transcriptionally repressive chromatin [ 98 ]. In retinoblastoma, HELLS overexpression is critical for ectopic proliferation and tumor progression [ 91 ]. Consequently, inactivation of the pRB pathway alters DNMTs activity, leading to aberrant genomic DNA methylation patterns and malignant progression.…”

MiR-365a-3p-Mediated Regulation of HELLS/GLUT1 Axis Suppresses Aerobic Glycolysis and Gastric Cancer Growth

“…Down-regulation of HELLS attenuates cell proliferation in glioma and colon cancer ( 25 , 26 ). HELLS is also required for tumor initiation and progression of retinoblastoma ( 27 ). Additionally, HELLS plays important roles in cell metabolism.…”