UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer

Qiangsheng Hu; Yi Qin; Shunrong Ji; Wenyan Xu; Wensheng Liu; Qiqing Sun; Zheng Zhang; Mengqi Liu; Quanxing Ni; Xianjun Yu; Xiaowu Xu

doi:10.1016/j.canlet.2019.03.024

UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer

Cancer Lett. 2019 Jun 28:452:226-236. doi: 10.1016/j.canlet.2019.03.024. Epub 2019 Mar 22.

Authors

Qiangsheng Hu¹, Yi Qin², Shunrong Ji¹, Wenyan Xu¹, Wensheng Liu¹, Qiqing Sun¹, Zheng Zhang¹, Mengqi Liu¹, Quanxing Ni¹, Xianjun Yu³, Xiaowu Xu⁴

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
² Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
³ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: yuxianjun@fudanpci.org.
⁴ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: xuxiaowu@fudanpci.org.

PMID: 30905812
DOI: 10.1016/j.canlet.2019.03.024

Abstract

UHRF1 (ubiquitin like with plant homeodomain and ring finger domains 1) is an epigenetic modifier that is overexpressed in some cancers, including pancreatic cancer, and mediates silencing of tumor suppressor genes. However, the role of UHRF1 in regulating pancreatic cancer metabolism and metastasis is not clear. In the present study, we demonstrated that silencing UHRF1 significantly inhibited aerobic glycolysis in pancreatic cancer cells. Furthermore, we demonstrated that UHRF1 knockdown decreased hypoxia inducible factor (HIF)1α levels and HIF1α targeted glycolytic genes. The Cancer Genome Atlas dataset analysis supported this observation. The Sirtuin (SIRT) family members regulate aerobic glycolysis in many cancers. We analyzed the correlation between UHRF1 and SIRT3-5 expression and found a significant negative correlation between UHRF1 and SIRT4. Further transcriptional and functional analysis demonstrates that SIRT4 is a downstream target of UHRF1 and negatively regulated aerobic glycolysis, cell proliferation and tumor growth. Our study identified a novel UHRF1/SIRT4 axis in regulation of pancreatic cancer cell proliferation, metabolism, and metastasis.

Keywords: Glycolysis; HIF1α; Pancreatic cancer; SIRT4; UHRF1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / physiology
CCAAT-Enhancer-Binding Proteins / genetics
CCAAT-Enhancer-Binding Proteins / metabolism*
Cell Line, Tumor
Cell Proliferation / physiology
Glycolysis / genetics
Glycolysis / physiology*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Mitochondrial Proteins / antagonists & inhibitors*
Neoplasm Metastasis / pathology
Oxygen Consumption / physiology
Pancreatic Neoplasms / pathology*
Sirtuins / antagonists & inhibitors*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

CCAAT-Enhancer-Binding Proteins
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Mitochondrial Proteins
UHRF1 protein, human
Ubiquitin-Protein Ligases
SIRT4 protein, human
Sirtuins