PLOD2 promotes aerobic glycolysis and cell progression in colorectal cancer by upregulating HK2

Abstract

The purpose of this study was to characterize the expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a membrane-bound homodimeric enzyme that specifically hydroxylates lysine in the telopeptide of procollagens, and assess the clinical significance of PLOD2 in colorectal cancer (CRC). Our results show that PLOD2 is highly expressed in CRC tumor tissues and cell lines, both at the mRNA and protein levels. Next, we found that PLOD2 was positively correlated with tumor grade (P = 0.001), T stage (P = 0.001), N stage (P < 0.001), and an advanced TNM stage (P < 0.001). Knockdown of PLOD2 attenuated CRC cell proliferation, migration, and invasiveness, in vitro. Our analysis of the mechanism behind the effects of PLOD2 suggests that PLOD2 affected glycolysis by regulating the expression of hexokinase 2 (HK2). HK2 reverses the inhibitory effects of PLOD2 knockdown in CRC. Furthermore, the data suggest that PLOD2 regulates the expression of HK2 via the STAT3 signaling pathway. Survival analysis revealed that high expression levels of PLOD2 (HR = 3.800, P < 0.001) and HK2 expression (HR = 10.222, P < 0.001) correlated with the overall survival rate. After analyzing their expression and correlation, PLOD2 positively correlated with HK2 (r = 0.590, P < 0.001). Our findings have revealed that PLOD2 is a novel regulatory factor in glucose metabolism, exerted via controlling HK2 expression in CRC cells, suggesting PLOD2 as a promising therapeutic target for CRC treatment.

Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells

“…Recent studies have reported that STAT3 might play a crucial role in maintaining glycolysis in cancer cells by regulating HK2 (Li et al, 2015;Liu and Yu, 2018). In CRC cells, using STAT3 phosphorylation inhibitor cryptotanshinone could significantly decrease the HK2 expression (Du et al, 2019). Also, siRNAknockdown STAT3 in CRC cells decreased mRNA levels of HK2 by reducing STAT3 recruitment to HK2 promoter (Du et al, 2019), consistent with the findings in breast cancer cells (Jiang et al, 2012).…”

“…In CRC cells, using STAT3 phosphorylation inhibitor cryptotanshinone could significantly decrease the HK2 expression (Du et al, 2019). Also, siRNAknockdown STAT3 in CRC cells decreased mRNA levels of HK2 by reducing STAT3 recruitment to HK2 promoter (Du et al, 2019), consistent with the findings in breast cancer cells (Jiang et al, 2012). On the basis of these observations, we assessed the importance of STAT3 signaling with regards to the ability of AT-I to mediate anticancer effects in CRC cells.…”

Recent developments in targeting genes and pathways by RNAi‐based approaches in colorectal cancer

“…STAT3 binding to the promoter region of HK2 regulates its expression in transcriptional level. The STAT3 knockdown using lipofectamine 2000 in SW480 cells decreased its recruitment to HK2 promoter and thereby, reduced HK2 expression 113 …”

“…More importantly, the knockdown of STAT3 substantially improved the chemosensitivity of LoVo cells to fluorouracil. 112 Du et al 113 investigated the effect of STAT3 silencing on hexokinase 2 (HK2) expression. HK2 enzyme catalyzes the conversion of glucose to 6-phosphate-glucose, the irreversible first stage of glycolysis.…”

“…The STAT3 knockdown using lipofectamine 2000 in SW480 cells decreased its recruitment to HK2 promoter and thereby, reduced HK2 expression. 113 In a study conducted by Ueno et al, 115 SW620 cells were transfected with MET siRNA using Oligofectamine.…”