SUMO wrestles SENP1 over response to hypoxia, providing possible cancer targets
Research under way on agent to stop SENP1 protein and strangle tumorsM. D. Anderson News Release 11/1/07
Researchers at the University of Texas MD Anderson Cancer Center have found a protein that enables cellular survival during periods of low oxygen, or hypoxia, which also is key for development of many kinds of cancer.
In the Nov. 2 issue of Cell, they report that this protein, known as SENP1 (Sentrin/SUMO-specific protease 1), might provide a basis for future targeted therapies. They have already started to develop an agent to stop SENP1 from working in cells, which could push a tumor to stop growing and to wither away.
"We believe this emerging pathway of biological regulation plays an important role in cancer development," says the study's lead author, Edward T. H. Yeh, M.D., professor and chair of the Department of Cardiology at M. D. Anderson Cancer Center.
"We had found earlier that high levels of SENP1 can be found in prostate cancer, but we didn't understand why," Yeh says. "Now, knowing that it regulates the entire hypoxic response, we believe it must play a role in other kinds of cancers."
Researchers believe tumors adapt to low oxygen levels caused by their own rapid growth by turning on molecules that help tumors build a new blood supply. Yeh and colleagues found that SENP1 is needed for that process and that inhibiting it might be one way to turn off tumor growth.
The work described in Cell is a continuation of a series of discoveries in the Yeh lab. The scientists discovered what they dubbed Sentrin and later named SUMO (Small Ubiquitin-related Modifier) proteins. Like their name suggests, these are mighty biological regulators that attach to other proteins in cells to modify their function or to move their location within a cell. Because they attach to many proteins and alter them, they resemble the well-known ubiquitin proteins which, by linking to proteins, target them for eventual break-down.
So far SUMO has been found to alter the function of more than 1,000 proteins, many of which are transcription factors - proteins in the cell nucleus that bind to DNA to help transcribe genetic information.
Yeh discovered SENP1, which snips SUMO off proteins. This dynamic process is called SUMOylation and deSUMOylation, and so far six different SENP family proteins have been found.
Although SENPs can reverse SUMOylation in many cases, their physiological role has not been well defined. In this paper, Yeh, and three colleagues sought to understand the role that SENP1 plays in normal development.
They bred mice to have a single copy of the SENP1 gene, instead of the normal two, and then they bred these mice again. Some of the offspring did not inherit any SENP1, and they all died between day 13 to 15 of the 21 day gestational period. "We found that they had a problem making red blood cells," Yeh says. "They could only make about one-fourth of the blood cells they needed, and that wasn't enough to sustain life."
They looked at why the blood cells were deficient, and found that at that critical stage, blood cells required erythropoietin (EPO), a hormone that regulates blood cell maturation. "If you don't have EPO, red blood cells will die because they cannot mature," he says. That led to their first discovery - that SENP1 regulates EPO.
Regulation of EPO depends on the blood's oxygen level, and in hypoxic conditions, which occurs at that stage of development, transcription factors known as hypoxia inducible factor1á (HIF1á) become active.
"These proteins enter the cell nucleus to turn on transcription of the EPO gene," Yeh says. They found that SENP1 controls EPO production by regulating one particular HIF protein, HIF1á. "When there isn't any SENP1, HIF1á is very unstable," he says. "It is not detectable in the embryo, compared to an embryo that has the SNEP1 gene."
It was already known that SUMO plays a role in the hypoxia process, Yeh adds. "We know that when you lower oxygen, HIF1á enters the cell's nucleus, and is quickly modified by SUMO."
But they discovered that there was one more step before HIF1á becomes active, producing EPO proteins to make more blood cells, and other proteins like VEGF that build more blood vessels to seek new sources of oxygen. They found that SENP1 needs to snip SUMO from SUMO-modified HIF1á before HIF1á can be active in transcription.
But that still didn't explain why HIF1á was missing in the nucleus of cells without SENP1. That led them to another, surprising finding - that if SENP1 does not clip off SUMO from SUMO-modified HIF1á when it is inside the nucleus, that SUMO then acts like ubiquitin, targeting destruction of HIF1á.
"This is the first example that SUMOylation of a protein can lead to its destruction," Yeh says. "That goes against the dogma we all believed in: that SUMO can change the location of a cell, but not degrade it. SUMO can do everything under the sun, including what ubiquitin can do. This vastly increases the functions of SUMOylation."
All this makes sense as far as cancer is concerned, Yeh says. HIF1á expression plays a role in many cancers and to date SENP1 has also found to be over-produced in prostate cancer. "This tells us that SENP1 is potentially involved in the overall regulation of tumorigenesis."
If true, Yeh says, that suggests it could become an Achilles heel for cancer. "These findings imply that you could inhibit SENP1 in tumors and let SUMO target HIF1á for destruction," Yeh says. "If tumors can't grow, these cancers could not continue to build a blood supply and grow and thrive."
The study was funded by grants from the National Institutes of Health and the U.S. Department of Defense. The other authors are all from the Department of Cardiology at M. D. Anderson: first author, Jinke Cheng, Ph.D., and Sui Zhang, M.D., Ph.D. Also participating was Xunlei Kang, M.D., a visiting student from Shanghai Jiao-Tong University School of Medicine. 11/01/07