# The role of PTEN feedback mechanism in cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $384,750

## Abstract

Project Summary
PTEN (phosphatase and tensin homolog) is among the most commonly altered tumor suppressor genes in
human cancers. The overarching premise of this project is twofold. First, while PTEN function can be
compromised by genetic mutations in inherited syndromes and sporadic cancers, post-translational
modifications (PTMs) of PTEN may play key roles in the dynamic regulation of PTEN function. Prior studies on
PTEN PTMs, including our work supported by this award, identified that deregulated ubiquitination and
deubiquitination lead to detrimental effects on PTEN stability and subcellular localization, thereby causing
tumorigenesis. Secondly, PTEN fulfils many of its tumor suppressive roles through the PI3K-AKT-mTOR
pathway; however, the role of PTEN has also been shown to extend beyond the control of PI3K, with PTEN
implicated in controlling genomic stability and cell cycle progression, although the mechanism remains unclear.
The overall goal of this application is to investigate the mechanisms of nuclear PTEN-mediated tumor
suppression, focusing on cancer-specific PTM regulation of PTEN compartmentalization and non-canonical
functions independent of its cytoplasmic phosphatase activity. Our new preliminary study revealed the novel
upstream PTM mechanism and essential downstream effectors for nuclear PTEN in cancer. Multi-omics
analyses of proteome, transcriptome and epigenome revealed a clear link between the PTEN-chromatin
remodeling factor axis and genomic integrity within the nucleus. Further, this novel PTEN-associated chromatin
remodeling factor conferred synthetic essentiality in cancer cells lacking nuclear PTEN. Based on these
observations, we hypothesize that canonical and non-canonical PTEN signaling coordinately reduces
tumorigenesis and therapy resistance. To test this hypothesis, we will (1) determine how PTEN PTMs occur
and their role in cancer; (2) define the non-canonical roles of PTEN in tumorigenesis and genomic instability;
(3) explore the therapeutic potential of the PTEN-chromatin remodeling factor axis in cancer. The completion of
this project will not only gain insight into the molecular and cellular mechanisms by which the newly
characterized PTM of PTEN tipping the balance between its canonical and non-canonical signaling, but also
yield critical information about the development of effective strategies for precision treatment of PTEN loss-of-
function driven cancers.

## Key facts

- **NIH application ID:** 10811733
- **Project number:** 5R01CA196740-07
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Min Sup Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,750
- **Award type:** 5
- **Project period:** 2016-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811733

## Citation

> US National Institutes of Health, RePORTER application 10811733, The role of PTEN feedback mechanism in cancer (5R01CA196740-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10811733. Licensed CC0.

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