LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2Research in context
Meijian Liao,
Weijie Liao,
Naihan Xu,
Bing Li,
Fuhai Liu,
Shikuan Zhang,
Yanzhi Wang,
Songmao Wang,
Yuanchang Zhu,
Deheng Chen,
Weidong Xie,
Yuyang Jiang,
Liu Cao,
Burton B. Yang,
Yaou Zhang
Affiliations
Meijian Liao
School of Life Sciences, Tsinghua University, Beijing 100084, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China
Weijie Liao
School of Life Sciences, Tsinghua University, Beijing 100084, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China
Naihan Xu
State Key Laboratory of Chemical Oncogenomics, Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Open FIESTA Center, Tsinghua University, Shenzhen 518055, PR China
Bing Li
School of Life Sciences, Tsinghua University, Beijing 100084, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China
Fuhai Liu
Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Open FIESTA Center, Tsinghua University, Shenzhen 518055, PR China
Shikuan Zhang
School of Life Sciences, Tsinghua University, Beijing 100084, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China
Yanzhi Wang
School of Life Sciences, Tsinghua University, Beijing 100084, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China
Songmao Wang
Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China
Yuanchang Zhu
School of Life Sciences, Tsinghua University, Beijing 100084, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China
Deheng Chen
Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518055, PR China
Weidong Xie
State Key Laboratory of Chemical Oncogenomics, Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Open FIESTA Center, Tsinghua University, Shenzhen 518055, PR China
Yuyang Jiang
State Key Laboratory of Chemical Oncogenomics, Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
Liu Cao
Key Laboratory of Medical Cell Biology, China Medical University, Shenyang 110013, PR China; Corresponding authors.
Burton B. Yang
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Corresponding authors.
Yaou Zhang
State Key Laboratory of Chemical Oncogenomics, Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Open FIESTA Center, Tsinghua University, Shenzhen 518055, PR China; Corresponding author at: State Key Laboratory of Chemical Oncogenomics, Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
Background: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. Methods: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. Findings: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. Interpretation: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer. Keywords: EPB41L4A-AS1, HDAC2, Glycolysis, Glutaminolysis, Cancer metabolism
