Interview with Dr. Dmitrovsky from the Geisel School of Medicine and the University of Texas

Oncotarget published "The ISG15-specific protease USP18 regulates stability of PTEN " which reported that using reverse-phase protein arrays, this study reports that engineered loss of the DUB USP18 destabilized the tumor suppressor protein phosphatase and tensin homologue in both murine and human lung cancer cell lines.

In contrast, engineered gain of USP18 expression in these same lung cancer cell lines stabilized PTEN protein.

Using the protein synthesis inhibitor cycloheximide, USP18 knockdown was shown to destabilize PTEN whereas USP18 overexpression stabilized PTEN protein.

Interestingly, repression of USP18 decreased cytoplasmic PTEN relative to nuclear PTEN protein levels.

There was a significant positive correlation and association between PTEN and USP18 protein expression profiles in human lung cancers.

Dr. Ethan Dmitrovsky from The Geisel School of Medicine at Dartmouth as well as The University of Texas MD Anderson Cancer Center said, "Lung cancer is the most common cause of cancer death for men and women. "

"Lung cancer is the most common cause of cancer death for men and women. "

Even though PTEN mutations are rare in lung cancer, PTEN protein is often lost in these tumors.

Interestingly, there is little correlation between PTEN mRNA and PTEN protein expression in studied cancers, implying that aberrant post-transcriptional or post-translational regulators of PTEN are engaged for its repression in tumorigenesis.

Reverse-phase protein arrays of lung cancer cell lines engineered with repressed USP18 expression uncovered PTEN as a potential target of the ISGylation pathway.

Immunoblotting of PTEN levels in murine and human lung cancer cell lines with engineered knockdown versus overexpression of USP18 established USP18 as a regulator of PTEN protein levels and stability.

Immunoprecipitation assays confirmed that ISG15 directly complexed with PTEN protein and this conjugation was attenuated by engineered overexpression of USP18. The translational relevance of this work was confirmed in human lung cancer arrays that revealed USP18 and PTEN immunostaining were positively correlated.

The Dmitrovsky Research Team concluded in their Oncotarget Research Output that this study elucidated PTEN as a new substrate of ISGylation.

Additional studies are needed to delineate the precise functional consequences of this ISGylation, uncover other ISGylated substrates, and learn in which cancers USP18 exerts a net oncogenic or tumor suppressive effect.

As these studies unfold, it is important to keep in mind that engineered loss of USP18 does reduce lung cancer formation in mouse models.

This is why identifying an inhibitor of USP18 is an important next step in the investigations of this DUB.

Likewise, it will be necessary to discover the antineoplastic effects of an inhibitor of USP18. Such an inhibitor could act as a single agent or in combination with another chemotherapeutic agent in lung and potentially other cancers.

DOI - https://doi.org/10.18632/oncotarget.13914

Full text - https://www.oncotarget.com/article/13914/text/

Correspondence to - Ethan Dmitrovsky - [email protected]

Keywords - ISG15, USP18, PTEN, protein stability, and lung cancer