Enhancer-Driven Gene KLK6 Promotes Radio-Resistance in Colorectal Cancer

Abstract

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. However, CRC treatment with radiotherapy often results in the development of radiation resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis of histone H3K27 acetylation (H3K27ac) revealed that enhancers play important roles in CRC. This study investigated the relationship between an active CRC enhancer and kallikrein-related peptidase 6 (KLK6) and its effect on CRC radiation resistance. Methods: Enhancer-driven genes in CRC were obtained from public H3K27ac ChIP-seq data and intersected with highly expressed genes in radioresistant CRC. The clinical roles of KLK6 in CRC and radiation resistance were analyzed using the standardized mean difference (SMD) model, summary receiver operating characteristic (SROC) curves, and Kaplan–Meier curves. The biological mechanisms of KLK6 were also explored using multiple computational biology algorithms and software such as R, STATA and SPSS. Results: The analysis of 58 H3K27ac ChIP-seq datasets revealed a total of 13,703 enhancer-regulated CRC genes. KLK6 was enhancer-driven and notably up-regulated in CRC tissues compared with non-CRC controls, exhibiting an SMD value of 1.03 (95% CI (confidence interval) = 0.68–1.38). Moreover, in radiation-resistance CRC, KLK6 expression was increased, exhibiting an SMD value of 0.29 (95% CI = 0.11–0.46) and an area under the curve (AUC) value of 0.74 (95% CI = 0.70–0.78). Additionally, KLK6 was associated with the immune microenvironment and was enriched in the ribosomal pathway of radioresistant CRC. Conclusions: The enhancer-regulated gene KLK6 is involved in radiation resistance in CRC patients.