Robust, tightly regulated DNA repair is critical to maintaining genome stability and preventing cancer. Eukaryotic DNA is packaged into chromatin, which has a profound, yet incompletely understood, regulatory influence on DNA repair and genome stability. The chromatin remodeler HELLS (helicase, lymphoid specific) has emerged as an important epigenetic regulator of DNA repair, genome stability, and multiple cancer-associated pathways. HELLS belongs to a subfamily of the conserved SNF2 ATP-dependent chromatin-remodeling complexes, which use energy from ATP hydrolysis to alter nucleosome structure and packaging of chromatin during the processes of DNA replication, transcription, and repair. The mouse homologue, LSH (lymphoid-specific helicase), plays an important role in the maintenance of heterochromatin and genome-wide DNA methylation, and is crucial in embryonic development, gametogenesis, and maturation of the immune system. Human HELLS is abundantly expressed in highly proliferating cells of the lymphoid tissue, skin, germ cells, and embryonic stem cells. Mutations in HELLS cause the human immunodeficiency syndrome ICF (Immunodeficiency, Centromeric instability, Facial anomalies). HELLS has been implicated in many types of cancer, including retinoblastoma, colorectal cancer, hepatocellular carcinoma, and glioblastoma. Here, we review and summarize accumulating evidence highlighting important roles for HELLS in DNA repair, genome maintenance, and key pathways relevant to cancer development, progression, and treatment.

Glioblastoma multiforme (GBM) is one of the most therapeutically refractory human cancers. Elevated cellular polyamine levels are a common feature of cancer cells, including GBM cells, and the polyamine pathway has been explored as a potential therapeutic target to inhibit polyamine biosynthesis or activate polyamine catabolism. In this study, we investigated the effect of N1,N11-diethyl-norspermine (DENSPM), a spermine analog that activates polyamine catabolism, in GBM cells. The in vitro cell culture experiments showed that DENSPM increased the sub-G1 apoptotic cell population in GBM cell lines but caused minimal cytotoxicity in normal astrocytes. Prior to apoptosis induction, DENSPM caused the elevation of spermidine/spermine N1-acetyltransferase (SSAT) expression accompanied by a decrease in polyamine levels and an increase of acetylated polyamine levels, which temporally coincided with the onset of hydrogen peroxide (H2O2) induction in the cells. The cytotoxic effects of DENSPM in the GBM cells could be partially attenuated by either turning down SSAT mRNA with small interference RNA or inhibiting H2O2 production with N1-acetylpolymine oxidase (APAO)/spermine oxidase (SMO) inhibitor. Though mitochondrial damage was induced, neither activation of the caspase cascade nor cytochrome c redistribution between the mitochondria and cytoplasm was observed. Systemic DENSPM treatment of mice with intracerebral GBM led to longer survival. Taken together, our studies indicate that DENSPM kills GBM cells through induction of SSAT coupled with H2O2 production, which is a potential target for GBM therapy.

Background/Objectives: Non-melanoma skin cancer (NMSC) is among the most common cancers in the United States, with solar ultraviolet (UV) radiation being a primary etiological factor. T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase activated by solar UV, has been implicated in skin carcinogenesis. This study aimed to investigate the mechanistic role of TOPK in solar UV-induced skin damage and tumor development. Methods: RNA sequencing (RNA-seq) was performed on skin tissues from wild-type (WT) and TOPK knockout (KO) mice, with or without solar UV exposure, to identify TOPK-regulated genes and pathways. Follow-up experiments using Western blotting, immunofluorescence, and luciferase assays were conducted in vitro and in vivo. Functional assays included 3D spheroid and Transwell co-culture systems involving cutaneous squamous cell carcinoma (cSCC) and fibroblast cells. Results: TOPK deletion altered gene expression profiles and inhibited solar UV-induced activation of multiple signaling pathways, including cytokine–cytokine receptor interaction, PI3K/AKT, MAPKs, PKG, cAMP, and calcium signaling. RNA-seq and protein analyses identified interleukin-19 (IL19) as a key downstream effector suppressed by TOPK deletion. In cSCC and fibroblast cells, TOPK knockdown reduced IL19 expression and secretion. IL19 promoted cSCC growth and activated PI3K/AKT, ERK, and TOPK pathways. Additionally, chronic TGFβ exposure increased IL19 expression and activated fibroblasts, as indicated by elevated αSMA and FAPα levels. Conclusions: These findings establish TOPK as a central regulator of solar UV-induced skin carcinogenesis, partially via modulation of IL19 signaling and fibroblast activation. Targeting TOPK may offer a novel strategy for the prevention and treatment of NMSC.