The POU2F1-ALDOA axis promotes the proliferation and chemoresistance of colon cancer cells by enhancing glycolysis and the pentose phosphate pathway activity

Abstract

Cancer metabolic reprogramming enhances its malignant behaviors and drug resistance, which is regulated by POU domain transcription factors. This study explored the effect of POU domain class 2 transcription factor 1 (POU2F1) on metabolic reprogramming in colon cancer. The POU2F1 expression was analyzed in GEO dataset, TCGA cohorts and human colon cancer tissues by bioinformatics and immunohistochemistry. The effects of altered POU2F1 expression on proliferation, glucose metabolism and oxaliplatin sensitivity of colon cancer cells were tested. The impacts of POU2F1 on aldolase A (ALDOA) expression and malignant behaviors of colon cancer cells were examined. We found that up-regulated POU2F1 expression was associated with worse prognosis and oxaliplatin resistance in colon cancer. POU2F1 enhanced the proliferation, aerobic glycolysis and the pentose phosphate pathway (PPP) activity, but reduced oxidative stress and apoptosis in colon cancer cells, dependent on up-regulating ALDOA expression. Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer. Our findings suggest that the POU2F1-ALDOA axis may be new therapeutic targets to overcome oxaliplatin resistance in colon cancer.

Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis

“…It can be seen by combining the specific position of five clusters from Figure 5 that early research around the year 2011, “study of tumor oxidative stress and inflammation signaling pathways and resistance mechanisms of different cancer types (cluster 4 and cluster 2)” had attracted a lot of attention in academia of this field. Afterward, “Study of cancer cell apoptosis pathway (cluster 1)” progressively gained importance around 2014, and some areas remain the hotpots until today, for example, “androgen receptor” (APY = 2018.82) ( 103 ), “glioblastoma” (APY= 2018.54) ( 79 ), and “transcription” (APY= 2018.15) ( 104 ). Notably, cluster 3 and cluster 5 (“study of cancer stem cells and autophagy”) are the two clusters that had the smallest APY compared with other clusters, and “metabolic reprogramming” (APY= 2019.39) ( 105 ), “microRNAs” (APY= 2019.05) ( 106 ) were mainly found lately.…”

The p52-ZER6/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway

“…Hence, the PPP allows tumor cells to defend themselves against increased ROS levels caused by a rapid metabolism, as well as meet the elevated demand for nucleic acid and fatty acid biosynthesis [ 6 , 7 , 27 ]. Furthermore, the PPP has attracted attention as a potential target for antitumor therapy [ 28 ]. Our study indicates that G6PD, the first rate-limiting enzyme of the PPP, is a target of p52-ZER6, which binds to the G6PD promoter and enhances its transcriptional activity.…”

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

“… 29 And the study of Lin et al found that POU2F1 directly bound to the ALDOA promoter and then decreased the sensitivity to oxaliplatin in colon cancer cells by enhancing glycolysis. 30 Furthermore, targeting metabolism reprogramming was an efficient method to overcome the chemoresistance of pancreatic ductal adenocarcinoma. 31 Consequently, targeting glycolysis has been indicated to be an effective means for overcoming chemoresistance, thereby improving cancer therapy.…”