SUMO wrestles SENP1 over response to hypoxia, providing possible cancer targets: research under way on agent to stop SENP1 protein and strangle tumors

Abstract

Researchers at the University of TexasM. D. Anderson Cancer Center have found a proteinthat enables cellular survival during periods oflow oxygen, or hypoxia, which also is key fordevelopment of many kinds of cancer.

In the Nov. 2, 2007 issue of Cell, they reportedthat this protein, known as SENP1(Sentrin/SUMO-specific protease 1), might providea basis for future targeted therapies. They havealready started to develop an agent to stop SENP1from working in cells, which could push a tumorto stop growing and to wither away.

"We believe this emerging pathway of biologicalregulation plays an important role in cancerdevelopment," says the study's lead author,Edward T. H. Yeh, M.D., professor and chair ofthe Department of Cardiology at M. D. AndersonCancer Center.

"We had found earlier that high levels of SENP1can be found in prostate cancer, but we didn'tunderstand why," Yeh says. "Now, knowing that itregulates the entire hypoxic response, we believeit must play a role in other kinds of cancers."

Researchers believe tumors adapt to low oxygenlevels caused by their own rapid growth byturning on molecules that help tumors build a newblood supply. Yeh and colleagues found that SENP1is needed for that process and that inhibiting itmight be one way to turn off tumor growth.

The work described in Cell is a continuation of aseries of discoveries in the Yeh lab. Thescientists discovered what they dubbed Sentrinand later named SUMO (Small Ubiquitin-relatedModifier) proteins. Like their name suggests,these are mighty biological regulators thatattach to other proteins in cells to modify theirfunction or to move their location within a cell.Because they attach to many proteins and alterthem, they resemble the well-known ubiquitinproteins which, by linking to proteins, targetthem for eventual break-down.

So far SUMO has been found to alter the functionof more than 1,000 proteins, many of which aretranscription factors - proteins in the cellnucleus that bind to DNA to help transcribegenetic information.

Yeh discovered SENP1, which snips SUMO offproteins. This dynamic process is calledSUMOylation and deSUMOylation, and so far sixdifferent SENP family proteins have been found.

Although SENPs can reverse SUMOylation in manycases, their physiological role has not been welldefined. In this paper, Yeh, and three colleaguessought to understand the role that SENP1 plays innormal development.

They bred mice to have a single copy of the SENP1gene, instead of the normal two, and then theybred these mice again. Some of the offspring didnot inherit any SENP1, and they all died betweenday 13 to 15 of the 21 day gestational period."We found that they had a problem making redblood cells," Yeh says. "They could only makeabout one-fourth of the blood cells they needed,and that wasn't enough to sustain life."

They looked at why the blood cells weredeficient, and found that at that critical stage,blood cells required erythropoietin (EPO), ahormone that regulates blood cell maturation. "Ifyou don't have EPO, red blood cells will diebecause they cannot mature," he says. That led totheir first discovery - that SENP1 regulates EPO.

Regulation of EPO depends on the blood's oxygenlevel, and in hypoxic conditions, which occurs atthat stage of development, transcription factorsknown as hypoxia inducible factor1á (HIF1α)become active.

"These proteins enter the cell nucleus to turn ontranscription of the EPO gene," Yeh says. Theyfound that SENP1 controls EPO production byregulating one particular HIF protein, HIF1α."When there isn't any SENP1, HIF1α is veryunstable," he says. "It is not detectable in theembryo, compared to an embryo that has the SNEP1gene."

It was already known that SUMO plays a role inthe hypoxia process, Yeh adds. "We know that whenyou lower oxygen, HIF1α enters the cell'snucleus, and is quickly modified by SUMO."

But they discovered that there was one more stepbefore HIF1α becomes active, producing EPOproteins to make more blood cells, and otherproteins like VEGF that build more blood vesselsto seek new sources of oxygen. They found thatSENP1 needs to snip SUMO from SUMO-modified HIF1αbefore HIF1α can be active in transcription.

But that still didn't explain why HIF1α wasmissing in the nucleus of cells without SENP1.That led them to another, surprising finding -that if SENP1 does not clip off SUMO fromSUMO-modified HIF1α when it is inside thenucleus, that SUMO then acts like ubiquitin,targeting destruction of HIF1á.

"This is the first example that SUMOylation of aprotein 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, butnot degrade it. SUMO can do everything under thesun, including what ubiquitin can do. This vastlyincreases the functions of SUMOylation."

All this makes sense as far as cancer isconcerned, Yeh says. HIF1α expression plays arole in many cancers and to date SENP1 has alsofound to be over-produced in prostate cancer."This tells us that SENP1 is potentially involvedin the overall regulation of tumorigenesis."

If true, Yeh says, that suggests it could becomean Achilles heel for cancer. "These findingsimply that you could inhibit SENP1 in tumors andlet SUMO target HIF1α for destruction," Yeh says."If tumors can't grow, these cancers could notcontinue to build a blood supply and grow andthrive."

The study was funded by grants from the NationalInstitutes of Health and the U.S. Department ofDefense. The other authors are all from theDepartment of Cardiology at M. D. Anderson: firstauthor, Jinke Cheng, Ph.D., and Sui Zhang, M.D.,Ph.D. Also participating was Xunlei Kang, M.D., avisiting student from Shanghai Jiao-TongUniversity School of Medicine.