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

Jinguan Lin,Nayiyuan Wu,Jiaxin Liang,Yiqing Yang,Linda Oyang,Qing Pan,Lixia Yang,Xiaohui Chen,Pin Yi,Min Su,Yanyan Tang,Shiming Tan,Shan Rao,Qianjin Liao,Yujuan Zhou,Xia Luo,Longzheng Xia,Yaqian Han

doi:10.1038/s41388-021-02148-y

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.

Highlights

Colon cancer is the third most common cancer worldwide and its incidence is rapidly increasing in developed countries [1]
We found that POU domain class 2 transcription factor 1 (POU2F1) over-expression up-regulated the glycolysis and the phosphate pathway (PPP) activity, we analyzed the potential expression of proliferating cell nuclear antigen (PCNA), but correlation between POU2F1 and glycolysis/PPP-related genes in decreased phosphorylated H2A histone family member X in HCT116 cells; POU2F1 silencing downregulated PCNA, but increased γ-H2AX expression in SW620 cells (Figs. 2H, I and S2D)
We found that POU2F1 transcripts were positively correlated with hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), aldolase A (ALDOA), pyruvate kinase M1/2 (PKM), lactate dehydrogenase A

Summary

INTRODUCTION

Colon cancer is the third most common cancer worldwide and its incidence is rapidly increasing in developed countries [1]. A recent study has revealed that up-regulated ALDOA expression promotes the proliferation, sphere formation, and radio-resistance of colorectal cancer cells [9]. It is still unclear how ALDOA expression is regulated and how ALDOA regulates glycolysis in colon cancer. POU2F1 can promote glycolytic metabolism and mitotic stability by promoting poised gene expression in colon cancer cells [13] It is still unclear how POU2F1 regulates glycolysis and promotes the progression of colon cancer. We employed the gain and loss of function strategies to determine the roles of POU2F1 and/or ALDOA in the glucose metabolism, proliferation and drug resistance of colon cancer in vitro and in vivo. To further understand the biological significance and mechanisms underlying the action of POU2F1 in colon cancer, we investigated

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

ETHICS APPROVAL AND CONSENT TO PARTICIPATE