Abstract
Abstract
Phosphatase and tensin homolog (PTEN) is one of the most commonly lost tumor suppressors in human cancers. Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer, and prostate cancer; and reduced expression is found in many other tumor types such as lung and breast cancer. PTEN is mostly found in the cytosol and it transiently associates with the inner surface of the plasma membrane and removes a phosphate group from phosphatidylinositol 3,4,5-trisphosphate (PIP3) and by this, it regulates various cellular functions. However in the nucleus, PTEN mediates phosphatase independent functions and is believed to be important for its tumor suppressive roles. Functional studies further confirm the transcriptional regulatory role of the PTEN; however, the process by which PTEN acts as a potential modulator of chromatin structure and histone modification is unexplored. We observed that the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a histone methyltransferase is upregulated in PTEN null mouse embryonic fibroblasts (MEFs) as compared to wild type counterparts, which suggested an inverse relation between EZH2 expression and PTEN expression. We further observed that phospho EZH2 levels (pEZH2ser21) were specifically upregulated in the PTEN null cells and coincided with the high pEZH2:EZH2 ratio in these settings, indicating that the majority of the upregulated EZH2 exists in the phosphorylated form. We also found that the pEZH2ser21 is mainly localized in the nucleus and only a small fraction exists in the cytoplasm, suggesting additional roles for pEZH2ser21 after partnering with cytoplasmic proteins. However, the non-phosphorylated form of the EZH2 is totally a nuclear protein under these conditions. Interestingly in PTEN null MEFs, transcriptional repression mark such as H3K27Me3 expression was downregulated with the simultaneous upregulation of H3K4Me3, an active transcription mark. Also, the increased expression of EZH2 primarily linked with the pause of active transcription, was associated with corresponding decrease in the H3K27Me3 repression mark which subsequently influenced the expression of various genes including senescence associated genes such as p21. Since, these aberrant histone methylation marks are hallmarks of various cancer pathologies, targeting EZH2 or its phosphorylation component could be a potential therapeutic strategy in cancers involving loss of PTEN. Taken together, these results demonstrate that in PTEN null processes, the pEZH2ser21 is capable of translocation, altering the histone marks and influencing genes associated with transcriptional repression and senescence. We also suggest that EZH2 could serve as important target for novel chemotherapeutics against cancers that are associated with loss of PTEN.
Citation Format: Abid Hamid, Mohammad Imran Khan, Vaqar Mustafa Adhami, Hasan Mukhtar. PTEN regulates polycomb repressive EZH2 expression and its deficiency correlates with active transcription mark H3K4Me3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 100. doi:10.1158/1538-7445.AM2015-100