2. Academic Validation
  3. Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy

  • Mol Cell. 2017 Jun 1;66(5):684-697.e9. doi: 10.1016/j.molcel.2017.04.026.
Xinjian Li 1,  Willie Yu 2,  Xu Qian 1,  Yan Xia 1,  Yanhua Zheng 1,  Jong-Ho Lee 1,  Wei Li 3,  Jianxin Lyu 4,  Ganesh Rao 5,  Xiaochun Zhang 6,  Chao-Nan Qian 7,  Steven G Rozen 2,  Tao Jiang 8,  Zhimin Lu 9
Affiliations

Affiliations

  • 1 Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2 Program in Cancer and Stem Cell Biology, Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
  • 3 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Institute of Enzyme Engineering and Medical Diagnosis, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 4 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Institute of Enzyme Engineering and Medical Diagnosis, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
  • 5 Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 6 Qingdao University Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao 266061, China.
  • 7 State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 8 Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
  • 9 Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: zhiminlu@mdanderson.org.
PMID: 28552616 DOI: 10.1016/j.molcel.2017.04.026
Abstract

Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for histone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is unclear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-mediated acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659, which exposed the nuclear localization signal of ACSS2 for importin α5 binding and nuclear translocation. In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and Autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, Autophagy, cell survival, and brain tumorigenesis. In addition, ACSS2 S659 phosphorylation positively correlates with AMPK activity in glioma specimens and grades of glioma malignancy. These results underscore the significance of nuclear ACSS2-mediated histone acetylation in maintaining cell homeostasis and tumor development.

Keywords

ACSS2; AMPK; TFEB; acetyl-CoA; autophagy; lysosomal biogenesis; nucleus; tumor development.

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