DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

Zhenzi Su; Aidi Gao; Xiaoqing Li; Shitao Zou; Chao He; Jinchang Wu; Wei-Qun Ding; Jundong Zhou

doi:10.3389/fonc.2021.706337

DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

Front Oncol. 2021 Jul 20:11:706337. doi: 10.3389/fonc.2021.706337. eCollection 2021.

Authors

Zhenzi Su¹, Aidi Gao², Xiaoqing Li², Shitao Zou², Chao He², Jinchang Wu^{1

3}, Wei-Qun Ding⁴, Jundong Zhou^{1

2}

Affiliations

¹ Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
² Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
³ The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
⁴ Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, United States.

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers with rapid progression and a high mortality rate. Our previous study demonstrated that DNA polymerase iota (Pol ι) is overexpressed in ESCC tumors and correlates with poor prognosis. However, its role in ESCC proliferation remains obscure. We report here that Pol ι promotes ESCC proliferation and progression through Erk- O-GlcNAc transferase (OGT) regulated Glucose-6-phosphate dehydrogenase (G6PD) overactivation. Cell clonogenic ability was assessed by colony formation assay. Cell proliferation was assessed by EdU incorporation assay. Our transcriptome data was reanalyzed by GSEA and validated by analysis of cellular metabolism, G6PD activity, and cellular NADPH concentration. The level of Pol ι, OGT, G6PD and O-GlcNAcylation in ESCC cells and patient samples were analyzed. The MEK inhibitor PD98059 was applied to confirm OGT expression regulation by the Erk signaling. The G6PD inhibitor polydatin was used to examine the role of G6PD activation in Pol ι promoted proliferation. We found that Pol ι promotes ESCC proliferation. It shunted the glucose flux towards the pentose phosphate pathway (PPP) by activating G6PD through OGT-promoted O-GlcNAcylation. The expression of OGT was positively correlated with Pol ι expression and O-GlcNAcylation. Notably, elevated O-GlcNAcylation was correlated with poor prognosis in ESCC patients. Pol ι was shown to stimulate Erk signaling to enhance OGT expression, and the G6PD inhibitor polydatin attenuated Pol ι induced tumor growth in vitro and in vivo. In conclusion, Pol ι activates G6PD through Erk-OGT-induced O-GlcNAcylation to promote the proliferation and progression of ESCC, supporting the notion that Pol ι is a potential biomarker and therapeutic target of ESCC.

Keywords: DNA polymerase iota; ESCC; Erk signaling pathway; G6PD activity; tumor proliferation.