Abstract
Regulation of RNA polymerase II (RNAPII)-mediated transcription controls cellular phenotypes such as cancer. Phosphatase and tensin homologue deleted on chromosome ten (PTEN), one of the most commonly altered tumor suppressors in cancer, affects transcription via its role in antagonizing the PI3K/AKT signaling pathway. Using co-immunoprecipitations and proximal ligation assays we provide evidence that PTEN interacts with AFF4, RNAPII, CDK9, cyclin T1, XPB and CDK7. Using ChIP-seq, we show that PTEN co-localizes with RNAPII and binds to chromatin in promoter and putative enhancer regions identified by histone modifications. Furthermore, we show that loss of PTEN affects RNAPII occupancy in gene bodies and further correlates with gene expression changes. Interestingly, PTEN binds to promoters and negatively regulates the expression of genes involved in transcription including AFF4 and POL2RA, which encodes a subunit of RNAPII. Loss of PTEN also increased cells’ sensitivity to transcription inhibition via small molecules, which could provide a strategy to target PTEN-deficient cancers. Overall, our work describes a previously unappreciated role of nuclear PTEN, which by interacting with the transcription machinery in the context of chromatin exerts an additional layer of regulatory control on RNAPII-mediated transcription.
Highlights
Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a dual specificity phosphatase that is inactivated or lost in a large proportion of human cancers, making it one of the most commonly mutated tumor suppressors [1,2]
Nuclear PTEN has been extensively studied in mouse embryonic fibroblasts (MEFs), where it was shown to be associated with chromatin [9,10,11]
In this study we identified a nuclear pool of PTEN that interacts directly with AF4/FMR2 family member 4 (AFF4) and directly or indirectly with RNA polymerase II (RNAPII), cyclin-dependent kinase 9 (CDK9), cyclin T1, XPB and cyclindependent kinase 7 (CDK7), which are components of different transcription complexes
Summary
Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a dual specificity phosphatase that is inactivated or lost in a large proportion of human cancers, making it one of the most commonly mutated tumor suppressors [1,2]. PTEN is best known for its function as a lipid phosphatase at the plasma membrane, where it dephosphorylates phosphatidylinositol-(3,4,5)-trisphosphate (PIP3), thereby antagonizing the phosphoinositide 3-kinase (PI3K) signaling pathway [3,4,5]. The loss of nuclear PTEN has been associated with more aggressive tumors and the malignant transformation of normal cells [6]. Lipid phosphoinositides and other components of the PI3K/AKT pathway have been found in the nucleus, only the cytoplasmic pools of PIP3 are sensitive to PTEN phosphatase activity [7]. Consistent with this, functions of nuclear PTEN, including homologous recombination-mediated repair of double-strand DNA breaks [8,9], cell proliferation, and chromatin condensation [10,11], are mostly independent of its lipid phosphatase activity
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