Enzyme That Allows Brain Tumor Growth Discovered

Summary: A new study reveals how the ACSS2 enzyme allows brain tumors to grow in a nutrient starved environment.

Source: MD Anderson Cancer Center.

New findings explain how the enzyme ACSS2 aids tumors in a nutrient-starved environment offering potential new treatment approaches.

All cancer tumors have one thing in common – they must feed themselves to grow and spread, a difficult feat since they are usually in a tumor microenvironment with limited nutrients and oxygen. A study at The University of Texas MD Anderson Cancer Center has revealed new details about how an enzyme called acetyl-CoA synthetase 2 (ACSS2) allows brain tumors to grow despite their harsh surroundings. The findings, published in the May 25 online issue of Molecular Cell, portends ACSS2 as a potential player in new approaches to treating this often deadly disease.

ACSS2 provides tumors a competitive edge by enhancing their ability to use a cellular salt called acetate as a carbon-based food source rather than the more desirable glucose which is often in short supply in cancer cells. This lifeline allows cancer cells at the core of the tumor to survive and even grow as it battles with nutrient deficiency.

Current therapies and the body’s own immune system are not efficient at stopping this vital nutrient pathway in cancer cells, and little is known about how these life-giving proteins are transported from cytosol, a liquid cell component, into the nucleus via a process called nuclear translocation. The ability to halt nuclear translocation of ACSS2 would cut off the cancer cell’s self-maintaining ability at its most basic level. The study, led by Zhimin Lu, Ph.D., professor of Neuro-Oncology, provided new information about nuclear translocation and how ACSS2 may offer a new approach for therapy.

“Overcoming metabolic stress is a critical step in solid tumor growth. Acetyl coenzyme A (CoA) generated via glucose and acetate uptake is a key carbon source for important cellular processes such as histone acetylation and gene expression,” said Lu. “However, how acetyl CoA is produced under nutritional stress is unclear. Our study explains the underlying mechanics of how this occurs, with ACSS2 as a novel and important method for gene expression under these circumstances.”

Using a CRISPR gene editing process, Lu’s team revealed what roles ACSS2 plays in histone acetylation by generation of nuclear acetyl-CoA from acetate within the cell’s nucleus. It also demonstrated the significance of histone modification via a metabolic enzyme in maintaining cell stability and tumor development. Histones are proteins that act as spools around which DNA winds and are crucial to gene regulation, while histone acetylation is a modification process critical to gene expression.

Image shows a brain and a red lump.
Study provides better understanding of how brain tumors ‘feed’. NeuroscienceNews.com image is adapted from the MD Anderson Cancer Center news release.

In essence, ACSS2 gives genetic permission for the production of lysosomes, cellular structures that serve as the cell’s waste disposal system, thus ridding the cell of unwanted materials, while recycling digested products for protein, DNA, and lipid synthesis. Lysosomes are recognized as a contributing factor in tumor development. ACSS2 also promotes a cannibalistic cell-feeding mechanism called autophagy, allowing lysosomes to receive, digest, and recycle much-needed nutrients. When nutrients located outside of the cell are limited, ACSS2 is able to reprogram cancer cell metabolism by increasing autophagy and reusing lysosome-digested products from unwanted or stored materials for cell survival and growth.

“These findings elucidate an instrumental interplay between reprogramming of metabolism and gene expression in cancer cells,” said Lu. “Inhibition of both ACSS2’s nuclear function and the metabolic pathway known as glycolysis, which converts glucose to tumor-feeding energy, appears to be an efficient approach for cancer treatment.”

About this neuroscience research article

MD Anderson research team members included Xinjian Li, Ph.D., Xu Qian, Ph.D., Yan Xia, Ph.D., Yanhua Zheng, Ph.D., and Jong-Ho Lee, Ph.D., all of Neuro-Oncology; and Ganesh Rao, M.D., Neurosurgery. Other participating institutions included Duke-NUS Medial School, Singapore; Wenzhou Medical University, Wenzhou, China; Qingdao University Cancer Institute, Qingdao, China; and San Yat-Sen University Cancer Center, Guangzhou, China.

Funding: The study was funded by the National Institutes of Health (CA109035, CA169603, CA204996, NS089754, CA016672 and CA127001); the James S. McDonnell Foundation 21st Century Science Initiative in Brain Cancer Research Award (220020318); the National Natural Science Foundation of China (8167282 and 81472386); the MD Anderson Odyssey Fellowship; the Anne Eastland Spears Fellowship in GI Cancer Research; the Caroline Ross Endowed Fellowship; and the Harold C. and Mary L. Daily Endowment Fund Fellowship. Lu is a Ruby E. Rutherford Distinguished Professor.

Source: Ron Gilmore – MD Anderson Cancer Center
Image Source: NeuroscienceNews.com image is adapted from the MD Anderson Cancer Center news release.
Original Research: Abstract for “Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy” by Xinjian Li, Willie Yu, Xu Qian, Yan Xia, Yanhua Zheng, Jong-Ho Lee, Wei Li, Jianxin Lyu, Ganesh Rao, Xiaochun Zhang, Chao-Nan Qian, Steven G. Rozen, Tao Jiang, and Zhimin Lu in Molecular Cell. Published online May 25 2017 doi:10.1016/j.molcel.2017.04.026

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]MD Anderson Cancer Center “Enzyme That Allows Brain Tumor Growth Discovered.” NeuroscienceNews. NeuroscienceNews, 26 May 2017.
<https://neurosciencenews.com/acss2-enzyme-brain-cancer-6775/>.[/cbtab][cbtab title=”APA”]MD Anderson Cancer Center (2017, May 26). Enzyme That Allows Brain Tumor Growth Discovered. NeuroscienceNew. Retrieved May 26, 2017 from https://neurosciencenews.com/acss2-enzyme-brain-cancer-6775/[/cbtab][cbtab title=”Chicago”]MD Anderson Cancer Center “Enzyme That Allows Brain Tumor Growth Discovered.” https://neurosciencenews.com/acss2-enzyme-brain-cancer-6775/ (accessed May 26, 2017).[/cbtab][/cbtabs]


Abstract

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

Highlights
•ACSS2 phosphorylation at S659 by AMPK induces nuclear translocation of ACSS2
•TFEB-associated ACSS2 binds to lysosomal and autophagy gene promoter regions
•Nuclear ACSS2 locally generates acetyl-CoA for H3 acetylation and gene expression
•Nuclear ACSS2 promotes lysosomal biogenesis, autophagy, and brain tumorigenesis

Summary

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.

“Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy” by Xinjian Li, Willie Yu, Xu Qian, Yan Xia, Yanhua Zheng, Jong-Ho Lee, Wei Li, Jianxin Lyu, Ganesh Rao, Xiaochun Zhang, Chao-Nan Qian, Steven G. Rozen, Tao Jiang, and Zhimin Lu in Molecular Cell. Published online May 25 2017 doi:10.1016/j.molcel.2017.04.026

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