| Summary: | Protein deubiquitinases <i>USP8</i> and <i>USP48</i> are known driver genes in corticotroph pituitary neuroendocrine tumors (PitNETs). <i>USP8</i> mutations have pleiotropic effects that include notable changes in genes’ expression. Genes involved in cell cycle regulation were found differentially expressed in mutated and wild-type tumors. This study aimed to verify difference in the expression level of selected cell cycle-related genes and investigate their potential role in response to cell cycle inhibitors. Analysis of 70 corticotroph PitNETs showed that <i>USP8</i>-mutated tumors have lower <i>CDKN1B</i>, <i>CDK6</i>, <i>CCND2</i> and higher <i>CDC25A</i> expression. <i>USP48</i>-mutated tumors have lower <i>CDKN1B</i> and <i>CCND1</i> expression. A lower p27 protein level in mutated than in wild-type tumors was confirmed that may potentially influence the response to small molecule inhibitors targeting the cell cycle. We looked for the role of <i>USP8</i> mutations or a changed p27 level in the response to palbociclib, flavopiridol and roscovitine in vitro using murine corticotroph AtT-20/D16v-F2 cells. The cells were sensitive to each agent and treatment influenced the expression of genes involved in cell cycle regulation. Overexpression of mutated <i>Usp8</i> in the cells did not affect the expression of p27 nor the response to the inhibitors. Downregulating or upregulating p27 expression in AtT-20/D16v-F2 cells also did not affect treatment response.
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