A protector for PTEN, a tumor-thwarting protein often missing in cancer cells, has emerged from research led by scientists at The University of Texas MD Anderson Cancer Center published online at Nature Cell Biology this week.
"We discovered that the enzyme USP13 stabilizes the PTEN protein by reversing a process that marks various proteins for destruction by the cell's proteasome," said the paper's senior author Li Ma, Ph.D., assistant professor of Experimental Radiation Oncology.
"USP13 also suppresses tumor formation and glycolysis though PTEN," Ma said. Glycolysis is a glucose metabolism pathway that tumors rely on to thrive and grow.
After establishing the relationship in cell lines and mouse model experiments, the team found low levels of USP13 in human breast tumors correlate with lower levels of PTEN. Both proteins were more abundantly present in normal breast tissue.
PTEN regulates cell growth and division. It also inhibits signaling by the AKT molecular pathway, which is involved in cell survival, metabolism and growth and is often overactive in human cancers.
This discovery provides a new way to think about PTEN deficiency and how it might be remedied. Ma noted the likely keys to possible treatment would be identifying druggable oncogenes that suppress USP13 in cancer cells, or hitting targets usually controlled by PTEN.
"In our paper, we showed that loss of USP13 leads to loss of PTEN and activation of AKT signaling, and that treatment of a breast cancer cell line with the AKT inhibitor MK-2206 can abolish the effect of USP13 loss on promoting tumor cell proliferation," Ma said. MK-2206 is actively being tested in clinical trials against a variety of cancers at MD Anderson and elsewhere, including advanced breast cancer.Genetic defects alone don't explain PTEN's absence
This suggested, Ma said, that regulation of PTEN after gene expression or after its translation into a protein "may contribute substantially to development of human breast cancer."
Ma and colleagues focused on ubiquitylation, a process that regulates proteins by attaching molecules called ubiquitins to them. When more than one ubiquitin is attached to a protein, a chain forms that is both a target and a handle for the proteasome – a protein complex that degrades proteins and recycles bits of them for other use.
Previous studies had revealed several proteins that attach ubiquitins to PTEN to initiate its destruction. Nothing had been identified that reverses that process for PTEN.Auditioning 30 DUBs to find one PTEN defender
A series of experiments showed that overexpressing USP13 in breast cancer cells:Increased PTEN expression and decreased cell multiplication and conversion to a cancerous state.
Knocking down USP13 in breast cancer cells increased cell multiplication and growth, while restoring either PTEN or USP13 completely reversed the effect.Lower USP13, larger tumors in mice
Ma and colleagues also analyzed USP13 and PTEN using human breast cancer progression tissue microarrays from the National Cancer Institute.Lower PTEN levels were found in 152 of 206 tumors (73.8 percent) and lower USP13 levels in 83 of 201 (41.3 percent).
"Our future studies aim to determine the physiological function of USP13 and how USP13 expression is lost in human cancer," Ma said.
Co-authors with Ma are first author Jinsong Zhang, Ph.D., Peijing Zhang, Ph.D., Hai-long Piao, Ph.D., Wenqi Wang, Ph.D., Min Wang, Dahu Chen, Ph.D. and Junjie Chen, Ph.D., of MD Anderson's Department of Experimental Radiation Oncology; Yongkun Wei, Ph.D., Yutong Sun, Ph.D., and Mien-Chie Hung, Ph.D., of MD Anderson's Department of Molecular and Cellular Oncology; and Subbareddy Maddika, Ph.D., of the Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad, India.
Grants from the National Cancer Institute of the U.S. National Institutes of Health (R00CA138572 and R01CA166051) and a Cancer Prevention and Research Institute of Texas Scholar Award to Ma funded this research. MD Anderson receives a cancer center support grant from the NCI (P30 CA016672).About MD Anderson
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