The Nuclear Face of PTEN: Implications in Cancer Prognosis and Targeted Therapy

Tumor suppressor Phosphatase and Tensin Homolog Deleted on Chromosome TEN (PTEN) shows a differential sub-cellular distribution, with its nuclear presence being particularly critical for its multifaceted tumor-suppressive functions. Nuclear PTEN mediates its arsenal of tumor suppressive actions viz., genomic stability maintenance, cell cycle regulation, DNA damage response, and transcriptional modulation, in both phosphatase-dependent and non-phosphatase-dependent manners. Diverse mechanisms exist to facilitate its nuclear import, including passive diffusion, active transport, and post-translational modifications such as monoubiquitination, phosphorylation, and SUMOylation as well as their crosstalk. Similarly, a number of mechanisms dictate the nuclear export of PTEN. Nucleo-cytoplasmic shuttling of PTEN is closely guarded by several protein factors. This review comprehensively explores the proteins involved in the transport and regulation of nuclear PTEN. Furthermore, it highlights the clinical significance of nuclear PTEN levels, which are closely associated with tumor grade, disease prognosis, and patient survival across multiple cancer types. By elucidating these mechanisms, this review underscores the importance of nuclear PTEN in cancer biology and its potential as a therapeutic target.