Featured Research

from universities, journals, and other organizations

Metabolic protein wields phosphate group to activate cancer-promoting genes

Date:
August 16, 2012
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
A metabolic protein that nourishes cancer cells also activates tumor-promoting genes by loosening part of the packaging that entwines DNA to make up chromosomes, according to scientists.

A metabolic protein that nourishes cancer cells also activates tumor-promoting genes by loosening part of the packaging that entwines DNA to make up chromosomes, a team led by scientists at The University of Texas MD Anderson Cancer Center reports in the Aug. 16 issue of Cell.

Working in cell lines and mouse models of glioblastoma multiforme, the most lethal form of brain tumor, senior author Zhimin Lu, Ph.D., associate professor of Neuro-Oncology at MD Anderson, and colleagues show that pyruvate kinase M2 (PKM2) fuels tumor growth by influencing a histone protein.

DNA is packaged in and spooled around histone proteins. The researchers found that PKM2 tags histone H3 with a phosphate group (one atom of phosphorus, four of oxygen) in a specific location called T11.

'No phosphorylation of H3, no tumor'

This phosphorylation leads to activation of the tumor-promoting genes, increased tumor cell reproduction and formation of tumors, Lu said. "If there's no phosphorylation of H3, there's no tumor. It's that crucial to glioblastoma formation."

An analysis of 85 human glioblastomas indicated that higher levels of PKM2 expression in the cell nucleus and of H3 phosphorylation are correlated with shorter survival. A separate analysis showed higher levels of H3 phosphorylation associated with higher grade tumors in a comparison of 30 low-grade tumor samples and 45 high grade glioblastomas.

"Histone 3-T11 phosphorylation has great potential to serve as both a prognostic marker and a guide for the use of PKM2-inhibiting therapies once they are developed," Lu said.

PKM2 has long been known for its well-established role in aerobic glycolysis -- the processing of glucose into energy that solid tumors, glioblastomas in particular, rely on heavily to survive and grow. Lu and colleagues have been teasing out the mechanisms of PKM2's other role -- the transcription and activation of genes.

It all starts with EGFR

When the epidermal growth factor receptor (EGFR) on the cell's membrane is activated by a growth factor, the PKM2 protein moves into the cell nucleus, where it binds to the promoter regions of genes. Other proteins called transcription factors attach to a gene's promoter region to activate it.

Cancer cells have high levels of EGFR on the cell surface, relaying growth signals from outside the cell inside. EGFR is itself a target of some cancer drugs.

A series of experiments by the research team uncovered the following molecular steps:

* After EGFR activation, PKM2 binds to histone H3 and attaches a phosphate group at T11.

* This separates another protein called histone deacetylase 3 (HDAC3) from the promoter regions of the genes CCND1 and MYC. HDACs block gene activation.

* With the HDACs gone, histone H3 acquires an acetyl group, which facilitates gene activation.

"This series of events only occurs when H3 is phosphorylated by PKM2," Lu said.

Blocking phosphorylation prevents brain tumors in mice

CCND1 expresses the protein cyclin D1, a cell cycle regulator. The MYC gene is frequently mutated in cancer, leading to overexpression of the transcription factor Myc, which in turn causes unregulated expression of many other genes.

Mouse experiments of EGFR-driven glioblastoma using reconstituted H3 histones, one normal and one with a mutant version of H3-T11A to prevent phosphorylation by PKM2, confirmed the relationship. Mice injected with normal, or wild type, H3, had an average tumor volume of nearly 40 cubic millimeters, while those with disabled T11A, blocking the phosphorylation point for PKM2, had no tumors.

"Our findings establish PKM2 as a histone kinase, which directly regulates gene transcription and controls cell cycle progression and proliferation of tumor cells" Lu said. Kinases are a class of proteins that attach phosphate groups to other proteins.

Co-authors with Lu are first author Weiwei Yang, Ph.D., Yan Xia, Ph.D., Xinjian Li, Ji Liang, Ph.D, and W.K. Alfred Yung, M.D., all of MD Anderson's Department of Neuro-Oncology; David Hawke, Ph.D., of MD Anderson's Department of Molecular Pathology, Kenneth Aldape, M.D., of MD Anderson's Department of Pathology; Dongming Xing of School of Life Sciences, Tsinghua University in Beijing; and Tony Hunter, Ph.D., of the Salk Institute for Biological Studies in La Jolla, Calif.

Project funding was provided by grants from the National Cancer Institute of the National Institutes of Health (CA109035, CA127001-03, CA082683) including MD Anderson's Cancer Center Support Grant (CA16672) and also by grants from the Cancer Prevention and Research Institute of Texas, the American Cancer Society and the Sister Institution Network Fund at MD Anderson.


Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Weiwei Yang, Yan Xia, David Hawke, Xinjian Li, Ji Liang, Dongming Xing, Kenneth Aldape, Tony Hunter, W.K. AlfredYung, Zhimin Lu. PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis. Cell, 2012; 150 (4): 685 DOI: 10.1016/j.cell.2012.07.018

Cite This Page:

University of Texas M. D. Anderson Cancer Center. "Metabolic protein wields phosphate group to activate cancer-promoting genes." ScienceDaily. ScienceDaily, 16 August 2012. <www.sciencedaily.com/releases/2012/08/120816133353.htm>.
University of Texas M. D. Anderson Cancer Center. (2012, August 16). Metabolic protein wields phosphate group to activate cancer-promoting genes. ScienceDaily. Retrieved July 24, 2014 from www.sciencedaily.com/releases/2012/08/120816133353.htm
University of Texas M. D. Anderson Cancer Center. "Metabolic protein wields phosphate group to activate cancer-promoting genes." ScienceDaily. www.sciencedaily.com/releases/2012/08/120816133353.htm (accessed July 24, 2014).

Share This




More Health & Medicine News

Thursday, July 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

New Painkiller Designed To Discourage Abuse: Will It Work?

New Painkiller Designed To Discourage Abuse: Will It Work?

Newsy (July 24, 2014) The FDA approved Targiniq ER on Wednesday, a painkiller designed to keep users from abusing it. Like any new medication, however, it has doubters. Video provided by Newsy
Powered by NewsLook.com
Doctor At Forefront Of Fighting Ebola Outbreak Gets Ebola

Doctor At Forefront Of Fighting Ebola Outbreak Gets Ebola

Newsy (July 24, 2014) Sheik Umar Khan has treated many of the people infected in the Ebola outbreak, and now he's become one of them. Video provided by Newsy
Powered by NewsLook.com
Condemned Man's US Execution Takes Nearly Two Hours

Condemned Man's US Execution Takes Nearly Two Hours

AFP (July 24, 2014) America's death penalty debate raged Thursday after it took nearly two hours for Arizona to execute a prisoner who lost a Supreme Court battle challenging the experimental lethal drug cocktail. Duration: 00:55 Video provided by AFP
Powered by NewsLook.com
China's Ageing Millions Look Forward to Bleak Future

China's Ageing Millions Look Forward to Bleak Future

AFP (July 24, 2014) China's elderly population is expanding so quickly that children struggle to look after them, pushing them to do something unexpected in Chinese society- move their parents into a nursing home. Duration: 02:07 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

    Health News

      Environment News

        Technology News



          Save/Print:
          Share:

          Free Subscriptions


          Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

          Get Social & Mobile


          Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

          Have Feedback?


          Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
          Mobile: iPhone Android Web
          Follow: Facebook Twitter Google+
          Subscribe: RSS Feeds Email Newsletters
          Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins