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Pilot study of combined aerobic and resistance exercise on fatigue for patients with head and neck cancer: Inflammatory and epigenetic changes.

ABSTRACT: This pilot study examined whether a combined aerobic resistance exercise program reduced fatigue and the potential inflammatory and epigenetic mechanisms in patients with head and neck cancer (HNC) receiving intensity-modulated radiotherapy. The exercise group (N = 12) received a 3-month supervised aerobic resistance exercise intervention that was initiated before a 6-week radiotherapy regimen; the control group (N = 14) received standard care. Fatigue was measured using Multidimensional Fatigue Inventory-20; physical function measures included a 6-minute walk distance (6MWD), chair stands, bicep curls, and hand grip strength. Inflammatory markers and DNA methylation data were acquired using standardized protocol. Patients were mostly white (93%) and male (81%) with a mean age of 57 years. At the end of the intervention, the exercise group had a marginal decrease in fatigue compared with the control (-5.0 vs. 4.9; P = 0.10). The exercise group had a significantly greater improvement in 6MWD (29.8 vs. -55.5 m; P = 0.04), and a marginally smaller decline in hand grip (-0.3 vs. -5.8 lbs; P = 0.05) at the end of the intervention than the control. No significant difference in inflammatory markers was observed between groups. Lower plasma interleukin (IL) 6, IL1 receptor antagonist, tumor necrosis factor α (TNFα), soluble TNF receptor II and C-reactive protein were significantly associated with increased 6MWD, chair stand, and bicep curl at the end of the intervention (p < 0.05). Among the 1152 differentially methylated sites (DMS) after intervention (p < 0.001), 163 DMS were located in gene promoter regions. Enrichment analysis suggested that the top 10 upstream regulators were associated with tumor (HNF4A, RPP38, HOXA9, SAHM1, CDK7, NDN, RPS15) and inflammation (IRF7, CRKL, ONECUT1). The top 5 diseases or functions annotations of the 62 hypermethylated DMS indicated anti-tumor and anti-inflammatory effects that might be linked to exercise. These findings suggest that exercise may improve physical performance and reduce fatigue, which could be further linked to decreased inflammation, during active radiotherapy for HNC patients. Larger studies are warranted.

SUBMITTER: Xiao C

PROVIDER: S-EPMC7415514 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) phenotype. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epigenetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. (2) Methods: We compared the DNA methylome and intracellular concentrations of tricarboxylic acid cycle metabolites in radioresistant FaDu and Cal33 cell lines with their parental controls, as well as aldehyde dehydrogenase (ALDH)-positive CSCs with negative controls. Moreover, we conducted a screen of a chemical library targeting enzymes involved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensitizing and CSC-targeting potential. (3) Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 trimethylation, heterochromatin formation, and gene silencing. The clonogenic survival assay after siRNA-mediated knock-down of both genes radiosensitized Cal33 and SAS cell lines. Moreover, high KDM6A expression in tissue sections of patients with HNSCC was associated with improved locoregional control after primary (n = 137) and post-operative (n = 187) radio/chemotherapy. Conversely, high KDM6B expression was a prognostic factor for reduced overall survival. (4) Conclusions: Within this study, we investigated cellular and molecular mechanisms underlying irradiation-induced cellular plasticity, a key inducer of radioresistance, with a focus on epigenetic alterations. We identified UTX (KDM6A) as a putative prognostic and therapeutic target for HNSCC patients treated with radiotherapy.

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Pilot study of combined aerobic and resistance exercise on fatigue for patients with head and neck cancer: Inflammatory and epigenetic changes.

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