Does normal expression of SPOP prevent development of many prostate cancers?


Researchers from the Mayo Clinic in Rochester, MN, are claiming that they have made a series of four important discoveries related to the role of a protein called “speckle-type POZ protein” (SPOP) and its involvement in the development of prostate cancer.

In the full text of their new paper in Cell Reports (also discussed in a blog post on the Mayo Clinic’s web site), An et al. state that

  • The antiandrogen receptor is a bona fide degradation substrate of SPOP.
  • Androgen receptor splicing variants are resistant to SPOP-mediated degradation.
  • Prostate cancer-associated SPOP mutants cannot bind to and promote androgen receptor degradation.
  • Androgens antagonize, but antiandrogens promote SPOP-mediated degradation of androgen receptor.

It is well understood that many of the most clinically significant forms of prostate cancer (i.e., the ones that go on to induce lethal, metastatic disease) are associated with  malfunctions of the androgen receptors — key cellular components that can bind to male hormones like testosterone and dihydrotestosterone.

Supposedly, SPOP gene mutations have been detected in about 15 percent of men with prostate cancer, and the SPOP protein is expressed at abnormally low levels in about 35 percent of prostate cancers.

What An et al. are effectively proposing is that SPOP, a protein that is often mutated in human prostate cancers, is an enzyme that selectively destroys androgen receptor protein; is a key regulator of androgen receptor activity that normally prevents uncontrolled growth of cells in the prostate; and thus SPOP normally helps to prevent the initiation of prostate cancer.

Low expression or non-expression of the SPOP would therefore result in over-expression of androgen receptors, leading to prostate cancer cell growth.

Clearly, as usual, such a finding needs to be confirmed by researchers from at least one other laboratory. However, if this finding can be confirmed by others, then Haojie Huang, PhD, the senior author of the new paper, would potentially be correct in his statement that

By uncovering this new and important pathway of androgen receptor destruction, we may one day be able to develop more effective treatments for a substantial proportion of prostate cancer patients who have developed resistance to standard antiandrogen therapy.

Of course it would also be the case that by identifying men with low levels of expression of SPOP, we might be able to identify men at heightened risk for development of prostate cancer, and it may be possible to stimulate expression of SPOP in such men.

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