Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.07.23.453217

EZH2 inhibition enhances TRAIL responses in multiple myeloma but not in quiescent cells

Arhoma, A.·Southan, J.·Chantry, A. D.·Haywood-Small, S. L.·Cross, N. A.
View original source ↗Export metadata ↓

Abstract

Multiple Myeloma is a plasma cell malignancy for which there is currently no cure, despite many novel therapies. TRAIL (Tumour necrosis factor-related apoptosis inducing ligand) is a promising anti-tumour agent although TRAIL-insensitive cells readily emerge when used as a single agent and its effects are limited due to many TRAIL-resistant cells which emerge soon after treatment. EZH2 is a H3K27 histone methyltransferase found to be overexpressed in many cancers including Multiple Myeloma. We tested the hypothesis that epigenetic reprogramming using the EZH2 inhibitor GSK343 would enhance TRAIL sensitivity, overcome TRAIL resistance, and target TRAIL-resistant quiescent cell populations. We show that GSK343 is a potent TRAIL sensitiser in TRAIL-sensitive RPMI 8226, NCI-H 929 and U266, and in TRAIL-resistant OPM-2 and JJN3, the latter showing very potent synergistic induction of apoptosis, primarily via caspase-8 activation but also via caspase-9. GSK343-enhancement of TRAIL responses was further enhanced in a 3D cell culture model of Multiple Myeloma in NCI-H 929 and U266. We show that in TRAIL-resistant sub-populations of Multiple Myeloma cells, GSK343 responses were completely attenuated in RPMI 8226 although synergistic enhancement of apoptosis was observed in NCI-H 929. Furthermore, following isolation of PKH26Hi quiescent cell populations, TRAIL responses and enhancement of TRAIL responses by GSK343 were completely attenuated. These studies show that EZH2 inhibition enhances TRAIL responses both in TRAIL-sensitive and TRAIL-resistant MM cell lines suspension culture and also in 3D cell culture to model the semi-solid Multiple Myeloma lesions in bone. Pre-existing TRAIL resistance was also enhanced by EZH2, and although synergistic enhancement of TRAIL responses by GSK343 was seen in NCI-H 929, responses were completely lost in TRAIL-resistant RPMI 8226 and also in quiescent cells. These studies highlight that although EZH2 inhibitors enhance TRAIL responses, acquired TRAIL resistance, and the presence of quiescent cells may mediate TRAIL-insensitivity in response to GSK343.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Arhoma, A., Southan, J., Chantry, A. D., Haywood-Small, S. L., Cross, N. A.. 2021-07-23. EZH2 inhibition enhances TRAIL responses in multiple myeloma but not in quiescent cells. https://doi.org/10.1101/2021.07.23.453217

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Glycolysis and interferon transcription in melanoma immunotherapy

Glycolysis and interferon signalling have both been associated with responses to PD-1 blockade, but their joint transcriptional relationship with treatment outcome remains uncertain. We examined whether a state with high glycolysis and low interferon- response was associated with reduced disease control in melanoma. Fixed Hallmark gene sets were scored by single-sample gene set enrichment analysis in GSE91061, GSE78220 and an additional Liu cohort. Disease control analyses included 47, 26 and 100 patients. Conditional odds ratios for the joint state were 6.06 (exact 95% confidence interval, 1.04 to 65.61), 0.35 (0.026 to 3.11) and 1.03 (0.39 to 2.73), respectively. Holm-adjusted P values for the two initial comparisons were 0.073 and 0.365. The additional exploratory P value was 1.000. Continuous models and analyses that omitted each patient in turn did not provide consistent evidence of an adverse association. IFN scores were negatively correlated with DNA-derived tumour purity in 102 patients (Spearman {rho} = -0.671). Among 40 patients with paired biopsies, disease control was associated with higher on-treatment IFN scores after baseline adjustment, although the paired subset had lower baseline glycolysis than patients without paired profiles. In patient-level single-cell analyses, the baseline CD8 T cell correlation weakened when an alternative rank score used a common gene background. The defined joint state was not consistently associated with poorer disease control across cohorts. Bulk IFN scores were related to tumour purity, and cellular correlations were sensitive to scoring choices. These transcriptomic results do not measure pyruvate concentration, glycolytic flux or STAT1 pyruvylation.

cancer biology↗
bioRxiv2026

Psychoneuroimmunology of Viral Hepatitis and Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Hepatocellular carcinoma (HCC) and viral hepatitis (VH) are recognized primarily as hepatic diseases, yet they impose a substantial neuropsychiatric disorders (NPDs) encompassing depression, anxiety, cognitive impairment, and fatigue. Whether these manifestations reflect psychological reactions or biologically grounded psychoneuroimmune dysfunction remains poorly understood. Here, we present a pre-registered systematic review and meta-analysis (PROSPERO 2026 CRD420251081757) synthesizing evidence from 24 studies combining psychosocial outcomes with immune dysregulation markers across HCC and VH populations. Bibliometric and network analyses identified a growing psychoneuroimmunology research hub linking cytokine signaling, microglial activation, blood-brain barrier (BBB) disruption, and gut-liver-brain axis dysregulation to the neuropsychiatric phenotype of these diseases. Meta-analysis revealed a pooled hazard ratio (HR) of 1.92 (95% CI: 1.09-3.39) for adverse outcomes in HCC and a pooled HR of 2.28 (95% CI: 1.48-3.52) for depression associated to genetic variants in VH. TNF-a, but not IL-6, showed a tendency toward lower levels in VH patients with versus without NPDs, suggesting differential inflammatory roles. The literature, however, remains fragmented by heterogeneous designs and a paucity of longitudinal data. A psychoneuroimmunological approach, integrating immune, endocrine, neural, and psychosocial dimensions, is essential for capturing the full systemic impact of HCC and VH and should inform future mechanistic research and multidisciplinary clinical strategies.

cancer biology↗
bioRxiv2026

Nutrient Availability as a Driver of Transcriptome Reprogramming in Osteosarcoma

Background: Gene expression in mammalian cells is intricately regulated by environmental and metabolic cues. Among these, nutrient availability represents a key feature of the tumor microenvironment and has recently emerged as a potent modulator of oncogenic signaling networks. In this study, we employed a cell-line model of osteosarcoma, a rare but highly aggressive bone malignancy affecting both humans and dogs. We demonstrate that altering the concentration of a single nutrient can profoundly reprogram gene expression in osteosarcoma cells, revealing a previously underexplored phenomenon: nutrient-dependent gene regulation. This finding highlights potential opportunities for therapeutic intervention and underscores the broader implications of metabolic regulation for personalized medicine and nutrition. Methods/Results: We performed bulk RNA sequencing of an established osteosarcoma cell line cultured under varying concentrations of two key nutrients, glucose and glutamine. Differential gene expression analysis revealed a pronounced nutrient-dependent transcriptional response. The identified genes were functionally associated with pathways involved in cancer, development, nervous system regulation, metabolism, cellular signaling, and immune responses. We identified seven distinct expression patterns, one of which exhibited a striking correlation with cell growth rate and resembled a FOS-like transcriptional signature. Notably, the proto-oncogene FOS was among the identified genes and displayed a strong growth-rate-dependent expression pattern. Conclusion/Impact: Our findings demonstrate that modulation of nutrient availability profoundly reshapes the gene expression landscape of osteosarcoma cells, revealing nutrient-responsive targets with potential therapeutic relevance. This work expands our understanding of metabolic regulation in cancer and suggests that nutrient-based interventions may provide a controllable means of influencing tumor progression. Beyond oncology, such approaches may also have broader implications for developmental biology, autoimmune disorders, and nervous system function. More broadly, this study highlights the potential of metabolic interventions as a strategy for targeted modulation of gene expression programs.

cancer biology↗