Reference Detail

Ref Type

Journal Article

PMID

(25946202)

Authors

Gong L, Govan JM, Evans EB, Dai H, Wang E, Lee SW, Lin HK, Lazar AJ, Mills GB, Lin SY

Title

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell cycle (Georgetown, Tex.)	14	14	2015	2323-32	Cell Cycle

URL

Abstract Text

The tumor suppressor, PTEN, is one of the most commonly mutated genes in cancer. Recently, PTEN has been shown to localize in the nucleus and is required to maintain genomic stability. Here, we show that nuclear PTEN, independent of its phosphatase activity, is essential for maintaining heterochromatin structure. Depletion of PTEN leads to loss of heterochromatic foci, decreased chromatin compaction, overexpression of heterochromatic genes, and reduced protein stability of heterochromatin protein 1 α. We found that the C-terminus of PTEN is required to maintain heterochromatin structure. Additionally, cancer-associated PTEN mutants lost their tumor-suppressor function when their heterochromatin structure was compromised. We propose that this novel role of PTEN accounts for its function in guarding genomic stability and suppressing tumor development.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
PTEN	Y336*	nonsense	loss of function	PTEN Y336* results in a premature truncation within the C2 tensin-type domain of the Pten protein at amino acid 336 of 403 (UniProt.org). Y336* inhibits Akt phosphorylation and associates with heterochromatin to similar levels of wild-type Pten, but fails to stabilize Hp1alpha protein and enhances Hp1alpha polyubiquitination, leading to satellite DNA overexpression, failure to suppress cell growth, arrest cycle cycle progression, or inhibit transformation in cultured cells (PMID: 25946202).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN Y336*	breast cancer	sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cells expressing PTEN Y336* demonstrated increased sensitivity to Talzenna (talazoparib) compared to cells expressing wild-type Pten in culture (PMID: 25946202}.	25946202