PTEN Tumor Suppressor Mechanisms in Human Cancers

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a pivotal tumour suppressor that regulates cell proliferation, survival and genome integrity through its lipid and protein phosphatase activities. By dephosphorylating the lipid second messenger PIP3, PTEN counteracts PI3K/AKT-driven pro-growth signals while also modulating nuclear processes such as DNA repair and chromatin organisation. PTEN function is intricately controlled by phosphorylation, ubiquitination, subcellular localisation and interactions with regulatory partners. Dysregulation of these controls by mutations, epigenetic silencing or post-translational modifications leads to aberrant activation of signalling pathways, metabolic rewiring and altered microenvironmental interactions that promote tumour initiation and progression. Recent studies have elucidated mechanisms by which PTEN stability and activity are fine-tuned, highlighting potential therapeutic avenues to restore its suppressive functions across diverse human cancers.

Research from Nature Portfolio

Dynamic phosphorylation of the PTEN C-terminal tail has been shown to create an oncogenic form of the protein that supports tumour growth. Mouse models carrying phosphomimetic mutations at key serine residues exhibit reduced PTEN stability and impaired inhibition of PI3K/AKT signalling, with consequent nuclear accumulation of β-catenin driving neoplastic proliferation in prostate tissue. Conversely, non-phosphorylatable variants maintain tumour suppression, emphasising the therapeutic potential of targeting PTEN tail phosphorylation. Complementary investigations have revealed a positive-feedback loop in which activated PI3K/AKT stabilises the MKRN1 E3 ubiquitin ligase, promoting PTEN ubiquitination and proteasomal degradation. In human tumours characterised by high AKT and MKRN1 expression, loss of PTEN correlates with poorer survival, underscoring the clinical relevance of post-translational regulation in maintaining PTEN function.

PTEN Tumor Suppressor Mechanisms in Human Cancers publication trend

The graph below shows the total number of articles in pten tumor suppressor mechanisms in human cancers across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphatidylinositol 3-kinase (PI3K): A lipid kinase that produces PIP3, initiating pro-growth and survival signalling cascades.

AKT: A serine/threonine kinase activated by PIP3, central to cell proliferation, survival and metabolism.

Hyperphosphorylation: Excessive addition of phosphate groups to specific protein residues, often altering function or stability.

Ubiquitination: Attachment of ubiquitin proteins to a target, marking it for proteasomal degradation.

Tumour dormancy: A reversible state of cell-cycle arrest in which cancer cells evade apoptosis and can later resume proliferation.

References

1. Hyperphosphorylated PTEN exerts oncogenic properties. Nature Communications (2023).
2. Chemotherapy-induced PTEN-L secretion promotes the selection of PTEN-deficient tumor cells. Journal of Experimental & Clinical Cancer Research (2024).
3. PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. Nature Communications (2015).
4. PTEN Tumor-Suppressor: The Dam of Stemness in Cancer. Cancers (2019).