Identification of super-enhancer-associated transcription factors regulating glucose metabolism in poorly differentiated thyroid carcinoma

Abstract This study aimed to uncover transcription factors that regulate super-enhancers involved in glucose metabolism reprogramming in poorly differentiated thyroid carcinoma (PDTC). TCA cycle and pyruvate metabolism were significantly enriched in PDTC. Differentially expressed genes in PDTC vs. normal control tissues were located in key steps in TCA cycle and pyruvate metabolism. A total of 23 upregulated genes localized in TCA cycle and pyruvate metabolism were identified as super-enhancer-controlled genes. Transcription factor analysis of these 23 super-enhancer-controlled genes related to glucose metabolism was performed, and 20 transcription factors were obtained, of which KLF12, ZNF281 and RELA had a significant prognostic impact. Regulatory network of KLF12, ZNF281 and RELA controlled the expression of these four prognostic target genes (LDHA, ACLY, ME2 and IDH2). In vitro validation showed that silencing of KLF12, ZNF281 and RELA suppressed proliferation, glucose uptake, lactate production and ATP level, but increased ADP/ATP ratio in PDTC cells. In conclusion, KLF12, ZNF281 and RELA were identified as the key transcription factors that regulate super-enhancer-controlled genes related to glucose metabolism in PDTC. Our findings contribute to a deeper understanding of the regulatory mechanisms associated with glucose metabolism in PDTC, and advance the theoretical development of PDTC-targeted therapies.

摘要 本研究旨在揭示调控低分化甲状腺癌（poorly differentiated thyroid carcinoma, PDTC）中参与糖代谢重编程的超级增强子（super-enhancers）相关转录因子（transcription factors）。三羧酸（TCA）循环与丙酮酸代谢在PDTC中显著富集。PDTC与正常对照组织的差异表达基因（differentially expressed genes）富集于TCA循环及丙酮酸代谢的关键环节。本研究共鉴定出23个定位于TCA循环及丙酮酸代谢通路的上调基因，均为超级增强子调控基因。针对这23个糖代谢相关的超级增强子调控基因开展转录因子分析，最终获得20个转录因子，其中KLF12、ZNF281与RELA具有显著的预后影响。由KLF12、ZNF281与RELA构成的调控网络可调控这4个预后靶基因（LDHA、ACLY、ME2及IDH2）的表达。体外验证实验显示，沉默KLF12、ZNF281与RELA的表达可抑制PDTC细胞的增殖、葡萄糖摄取、乳酸生成及ATP水平，同时升高ADP/ATP比值。综上，本研究鉴定出KLF12、ZNF281与RELA为调控PDTC中糖代谢相关超级增强子靶基因的关键转录因子。本研究结果有助于深入阐明PDTC糖代谢相关调控机制，推动PDTC靶向治疗的理论进展。