Phosphatase-dependent function of PTEN in maintaining mitotic chromatin condensation

Abstract

The process for genetic transmission takes place in a chromatin environment constituted of histones and non-histone architectural proteins. PTEN, a potent tumor suppressor defective in a large number of human cancers, has been found to interact with various chromatin components, guarding the genome against chromosome instability. Studies have shown that PTEN-deficient cells exhibit a globally defective chromatin environment. However, a comprehensive understanding of how the dynamic process of mitotic chromosome condensation is impacted by the PTEN-deficient epigenetic milieu is needed. Thus, the purpose of this study was to identify aberrations of dynamic mitotic chromatin compression resulting from PTEN dysfunction and to evaluate the importance of PTEN phosphatase activity in maintaining heterochromatin stability. An intrinsic metaphase structure assay was utilized to monitor the structural integrity of chromosomes in murine MC38 colon cancer cells. Following successive cycles of condensation and decondensation, MC38 cells with and without Pten were subjected to analysis of chromosome morphology. Pten-/cells exhibited fewer heterochromatic centers as compared to Pten+/+ cells. Ectopic expression of wild-type Pten (WT) rescued the aberrant heterochromatic morphology in Pten-null cells. In contrast, a lipid phosphatase deficient Pten mutant G129E (GE) failed to correct the Pten-deficient chromatin aberrations. These observations reveal that PTEN plays an essential role in maintaining mitotic chromosome stability and suggest that epigenetic approaches may be implemented to correct mitotic chromatin deregulation in tumors carrying PTEN mutations.