Heavenly HELLS? A potential new therapeutic target for retinoblastoma.

Abstract

Although the role of the retinoblastoma protein (pRB) in cell cycle control has been extensively studied, druggable targets downstream of pRB remain to be identified. Retinoblastoma is the most common childhood intraocular malignancy caused by bi-allelic inactivation of the retinoblastoma gene (RB1). Despite recent progress in clinical outcomes of retinoblastoma, enucleation (eye removal) remains a frequent treatment for retinoblastoma and the survival rate for metastatic retinoblastoma is just over 10%. Thus, there is a pressing clinical need to determine the factors responsible for tumor progression following RB1 inactivation in order to facilitate the development of new therapeutic strategies. Furthermore, the loss of pRB function contributes to a wide array of human cancers. A few years ago, we elucidated how tumors progress quickly following RB1 inactivation, showing that while the retinoblastoma genome is stable – with RB1 being the only known tumor suppressor gene mutated – multiple cancer pathways can be deregulated epigenetically [1]. HELLS (helicase, lymphoid specific; also known as LSH, ICF4, PASG, and SMARCA6) belongs to the SNF2 family of chromatin-remodeling ATPases. It remodels chromatin to allow accessibility of DNMT3A or DNMT3B to DNA in order to support de novo DNA methylation and stable gene silencing during cellular differentiation [2]. We have previously identified that upregulation of HELLS following RB1 inactivation could cause the epigenetic gene expression deregulation that results in tumorigenesis [3]. HELLS has an interesting connection to the RB/E2F pathway: the HELLS gene is a direct target of E2F1 [4] and HELLS protein interacts with E2F3 at several E2F target genes that control cell cycle entry [5,6]. Similar to what we observed in retinoblastoma, depletion of HELLS in glioblastoma and several carcinomas impairs tumor growth, suggesting that HELLS may contribute to the malignant progression of various tumors. We have also reported that HELLS is overexpressed in osteosarcoma; however, we found no evidence of HELLS serving as a driver of malignancy in these tumors [7]. The osteosarcoma study offered a precautionary perspective indicating that while HELLS level may reflect RB/E2F pathway inactivation, its upregulation may not always be synonymous with a critical role in tumor formation or tumor maintenance across all malignancies, and therefore should not be a Research Perspective