Advancing the Science

Mayo Clinic Medical Science Blog – an eclectic collection of research- and research education-related stories: feature stories, mini news bites, learning opportunities, profiles and more from Mayo Clinic.

August 8, 2018

New pathway in prostate cancer cells suggests possible therapy

By Sara Tiner

Expanding on previous findings, a group of Mayo researchers continue using discovery research in cells to find options for treating cancers. In their most recent paper, published in Molecular Cell, the team's research suggest that a drug used for breast cancer may be helpful in some types of prostate cancers.

"In the current study we show that in prostate cells, an overexpressed enzyme called DUB3 causes [drug] resistance due to the increased levels of a protein called BRD4," says senior author and Mayo Clinic molecular biologist Haojie Huang, Ph.D.

Bromodomain and extra-terminal domain inhibitors are drugs that prevent the action of BET proteins, an important task because these proteins help fuel cancer cells. BRD4 is a BET protein and enzymes like DUB3 fuel the protein's action. Dr. Huang explains that researchers already knew that DUB3 required the action of another group of enzymes called cyclin-dependent kinases, or CDKs.

In this paper, the scientists report that blocking CDK4 and CDK6 needed by the enzyme DUB3, decreases BRD4 protein levels in prostate cancer cells.

"Given that CDK4/6 inhibitor is already in clinical use, our findings could lead to immediate clinical trials for treatment of DUB3-overexpressed prostate cancer by combined use of BET and CDK4/6 inhibitors," says Dr. Huang.

This research also presents a mystery.

In their article published last year in Nature Medicine, Dr. Huang and team reported on a new biomarker that could be used to improve outcomes in some prostate cancers. The researchers explained how resistance to one class of drug can develop from mutations within the SPOP gene, which is frequently altered in primary prostate cancer and often causes resistance to drugs called BET-inhibitors.

“Based on our findings, SPOP gene mutation or elevated BET protein expression can now be used as biomarkers to improve outcome of BET inhibitor-oriented therapy of prostate cancer with SPOP mutation or BET protein overexpression,” says Dr. Huang.

In the current study, the researchers had expected that in SPOP mutated cells, blocking DUB3 would not increase the sensitivity of the cells to BET inhibitors and decrease the levels of BDR4 in cells. However, Dr. Huang says, that was actually what they found.

"It is very exciting because it not only highlights the existence of another enzyme that can cause BRD4 protein destruction, but also emphasizes that inhibition of DUB3 by CDK4/6 inhibitors can be harnessed to overcome BET inhibitor resistance in SPOP-mutated prostate cancer, which was the major finding of our study published previously," explains Dr. Huang.

As for next steps, this effort produced a clear horizon.

"In the current study we provide evidence that there exists an unidentified enzyme mediating BRD4 protein destruction in a manner independent of SPOP and that warrants further investigation," says Dr. Huang.

In addition to Dr. Huang, other authors are: Xi Jin, M.D., Ph.D.; Yuqian Yan, Ph.D; Dejie Wang, Ph.D.; Donglin Ding, Ph.D.; Tao Ma; Zhenqing Ye, Ph.D.; Rafael Jimenez, M.D.; Liguo Wang, Ph.D.; and Heshui Wu, M.D.

Funding for this work was provided by the National Institutes of Health and the National Natural Science Foundation of China.

Tags: basic science, biomedical research, gene mutation, Haojie Huang, Mayo Clinic Cancer Center, News, prostate cancer

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