New function for colon cancer gene found
Dartmouth Medical School research reveals new role for gatekeeper gene APC
Dartmouth Medical School geneticists have discovered a striking turnabout role for a gatekeeper
known to put on the brakes for colon cancer. Flaws in a gene called adenomatous polyposis coli
(APC), which normally prevents excessive cell growth, are thought to trigger development of
most colorectal cancers.
But in an about face, the tumor suppressor gene also has a second task, the researchers found, as a
gas pedal that accelerates signaling between cells. This novel duality is reported in the January 18
issue of Science by a team led by Dr. Yashi Ahmed, assistant professor of genetics at DMS.
Colon cancer is the second most frequent cause of cancer-related death in the United States,?said
Ahmed. Understanding the normal role of APC and what’s happening to cells that have lost the
gene can help us identify therapeutic targets for drug action against this common cancer.?
APC was first identified in families with a hereditary predisposition to develop colon cancer.
Family members are born with an error in one of their two APC gene copies, but are fine as long
as the other gene copy is normal. However, many of their colon cells develop a second defective
gene. As a result, by their teens and twenties these individuals get hundreds to thousands of colon
growths--called polyps--some of which invariably progress to cancer, so their colon is usually
removed when they are in their twenties.
But these types of polyps that have a strong association with cancer are not limited to hereditary
colon cancer. By age 60, according to Ahmed, up to 40 percent of the general population will have
at least one such polyp with mutations in both APC genes. Fortunately, with a colonoscopy to
view the colon many polyps can be removed in their early stages, before they become cancer.
APC is part of a vital signaling pathway that coordinates cell growth in all animals from flies
through people. During embryonic development, this pathway causes cells to grow and
differentiate to become the kind of cells they should be. In many adult cells, however, the pathway
should be turned off, and APC puts the brakes on the pathway to stop cell growth.
The researchers devised strategies to explore the molecular workings of APC in the fruit fly, a
simple animal with rapid breeding time that offers many advantages in the laboratory. When they
remove or reduce APC, they see fruit flies with no wings, peculiar abdomens and many other
oddities.
However, APC defects found in colonic polyps have an unusual feature. Generally, gene mutations
can disrupt an entire protein, but in colon cancers, only half the APC protein is lost, while the
other half remains, Ahmed explains. Her work in fruit flies suggests a reason for this unexplained
phenomenon.
We found that APC has a second, new job. It not only puts the brake on cell signaling, but also
gives some gas. These two functions are controlled by different parts of the protein. In the colon
cancers, the brake part of the APC protein is lost, but there is strong pressure to retain the
give-it-some-gas portion,?Ahmed said.
Indeed, the DMS team’s data suggest that this new as?facet is also present in the human APC
protein, reinforcing APC’s role as a regulator that promotes or suppresses cell growth. Future
studies on how APC balances signals may help benefit treatments not only for colon tumors, but
also for birth defects, since the signaling pathway regulated by APC affects nearly all tissues
during development.
###
Co-authors, all from Ahmed’s laboratory team, are: Carter M. Takacs, Jason R. Baird, Edward G.
Hughes, Sierra S. Kent, Hassina Benchabane and Raehum Paik. For more information, contact
Ahmed, at 603-650-1937 or email at: yashi. ahmed@dartmouth.edu.
For copies of the please contact the the AAAS Office of Public Programs at 202-326-6440 or
scipak@aaas.org.
11Cancer stem cell marker also drives transcription in normal cells
New research links the recently discovered function of a multi-faceted transcriptional complex to
control of gene expression in both normal cells and cancer stem cells. Two separate studies,
published by Cell Press in the January 18th issue of Molecular Cell, provide insight into novel
subunits associated with an evolutionarily conserved transcriptional regulatory complex and reveal
a previously undescribed chromatin function that is required for full activity of nuclear receptors
in normal cells and for the MYC oncoprotein in tumor cells.
Initiation of transcription requires sophisticated coordination of many different regulatory factors.
Coactivators are multi-subunit complexes that facilitate transcription initiation directly, by
interacting with RNA polymerase and general transcription factors, or indirectly, by influencing
chromatin. For example, histone acetyltransferase (HAT) complexes are thought to activate gene
expression by modifying chromatin-associated proteins called histones which function like spools
for DNA to wind around.
The yeast SAGA complex and the homologue metazoan TFTC/STAGA, also called hSAGA, are
HAT-containing complexes that facilitate access of general transcriptional factors to DNA through
histone acetylation. Although hSAGA is thought to be a homologue of the well-studied yeast
SAGA complex, its subunit composition and functions are not as well understood. Dr. Didier
Devys from the Institute de G uique et de Biologie Moleulaire et Cellulaire in Strasbourg, France
and colleagues identified three novel subunits, ATXN7L3, USP22 and ENY2, that are homologues
of previously described subunits in the yeast SAGA complex.
The researchers demonstrated that the newly identified subunits work together to remove the
ubiquitin moiety from monoubiquitylated histone H2B, similarly to what has been previously
described in yeast, but also remove the ubiquitin moiety from monoubiquitylated histone H2A.
The latter modification is not found in yeast but is more prevalent than monoubiquitylated H2B in
mammals. Importantly, the deubiquitylation module of the Drosophila TFTC/STAGA complex
was an enhancer of position effect variegation and counteracted heterochromatin silencing while
both the Drosophila and the human deubiquitylation module were shown to be required for full
transcriptional activation by the androgen receptor. This finding is clinically significant as
androgen receptor activity is often deregulated in prostate cancer.
The association of both HAT and deubiquitylation activities in the hSAGA complex provide an
attractive mechanism by which the so called cross-talk?between given histone marks is
coordinated within the same regulatory complex?says Dr. Devys. Further mechanistic studies are
essential to examine the exact link between these activities and other chromatin modifying
complexes to understand how these sequential events participate in chromatin remodeling and
gene activation.?/p>
Working in parallel, a second research group led by Dr. Steven B. McMahon from Thomas
Jefferson University’s Kimmel Cancer Center in Philadelphia also identified USP22 as a member
of hSAGA. Previous work had identified USP22 as part of an eleven gene cancer stem cell
signature that accurately distinguished patients whose tumors would eventually metastasize from
those whose tumors would remain localized. Unlike the other genes in this cancer stem cell
signature, no direct mechanistic link to human cancer has been ascribed to USP22,?explains Dr.
McMahon. McMahon’s group demonstrated that USP22 is required for activation of target gene
transcription by the MYC oncoprotein and that USP22 depletion compromises MYC functions,
including transformation of mammalian cells, and leads to cell cycle arrest.
Taken together, these results significantly advance the understanding of mechanisms that permit
fine-tuning of transcriptional regulation by revealing that the hSAGA histone acetyltransferase
complex is also capable of histone deubiquitylation. The findings provide critical new information
about the importance of the timing and sequence of chromatin modifications in the control of gene
expression in normal cells and shed light on the biochemical function of cancer stem cell marker
and hSAGA subunit USP22, identifying it as a potential therapeutic target.
###
Zhang et al.:
The researchers include Xiao-Yong Zhang,The Department of Cancer Biology, The Kimmel
Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA, USA; Maya Varthi,The
Department of Cancer Biology, The Kimmel Cancer Center, Thomas Jefferson Medical College,
Philadelphia, PA, USA; Stephen M. Sykes, The University of Pennsylvania School of Medicine,
Philadelphia, PA, USA; Charles Phillips, The Department of Cancer Biology, The Kimmel Cancer
Center, Thomas Jefferson Medical College, Philadelphia, PA, USA; Claude Warzecha, The
University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Wenting Zhu, The
University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Anastasia Wyce, The
University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Alan W. Thorne,
University of Portsmouth, Portsmouth, UK; Shelley L. Berger, The Wistar Institute, Philadelphia,
PA, USA; and Steven B. McMahon, The Department of Cancer Biology, The Kimmel Cancer
Center, Thomas Jefferson Medical College, Philadelphia, PA, USA.
Zhao et al.:
The researchers include Yue Zhao, Laboratory of Nuclear Signaling, Institute of Molecular and
Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Guillaume Lang, Institut de
Genetique et de Biologie Moleculaire et Cellulaire, Universite?Louis Pasteur de Strasbourg,
Strasbourg, France; Saya Ito, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular
Biosciences, The University of Tokyo, Tokyo, Japan; Jacques Bonnet, Institut de Genetique et de
Biologie Moleculaire et Cellulaire, Universite?Louis Pasteur de Strasbourg, Strasbourg, France;
Eric Metzger, Universitats-Frauenklinik und Zentrum fur Klinische Forschung, Klinikum der
Universitat Freiburg, Freiburg, Germany; Shun Sawatsubashi, Laboratory of Nuclear Signaling,
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Eriko
Suzuki, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The
University of Tokyo, Tokyo, Japan; Xavier Le Guezennec, Department of Molecular Biology,
NCMLS, Radboud University Nijmegen, Nijmegen, The Netherlands; Hendrik G. Stunnenberg,
Department of Molecular Biology, NCMLS, Radboud University Nijmegen, Nijmegen, The
Netherlands; Aleksey Krasnov, Institute of Gene Biology, Russian Academy of Sciences, Moscow,
Russia; Sofia G. Georgieva, Institute of Gene Biology, Russian Academy of Sciences, Moscow,
Russia; Roland Schule, Universitats-Frauenklinik und Zentrum fur Klinische Forschung,
Klinikum der Universitat Freiburg, Freiburg, Germany; Ken-Ichi Takeyama, Laboratory of
Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo,
Tokyo, Japan; Shigeaki Kato, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular
Biosciences, The University of Tokyo, Tokyo, Japan; Laszlo?Tora, Institut de Genetique et de
Biologie Moleculaire et Cellulaire, Universite?Louis Pasteur de Strasbourg, Strasbourg, France;
and Didier Devys, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Universite?Louis
Pasteur de Strasbourg, Strasbourg, France.
Zhang et al.: The Cancer Stem Cell Marker USP22 Is a Subunit of the Human SAGA Complex
Required for Activated Transcription and Cell-Cycle Progression," and Zhao et al.: TFTC/STAGA
Module Mediates Histone H2A and H2B Deubiquitination, Coactivates Nuclear Receptors, and
Counteracts Heterochromatin Silencing.?/p>