G9a Regulates Cell Sensitivity to Radiotherapy via Histone H3 Lysine 9 Trimethylation and CCDC8 in Lung Cancer

Abstract

Purpose To investigate the role and underlying mechanism of G9a and CCDC8 in lung cancer radioresistance. Methods Western blotting assays were used for G9a, CCDC8, H3K9me3 expression detection. MTT assays and clone formation assays were used for measuring cell proliferation activities. Flow cytometry assays were used for cell apoptosis detection. The enrichment of H3K9me3 in CCDC8 promoter was measured by chromatin immunoprecipitation assay. Results G9a and G9a-mediated H3K9me3 are upregulated in radioresistant lung cancer cells (A549/IR cell and XWLC-05/IR cell). Blocking G9a not only promotes radiosensitivity of A549/IR cell and XWLC-05/IR cell but also reduces aggressive behavior of radioresistant A549 cell/IR and XWLC-05/IR cell. In addition, G9a-controlled H3K9me3 is able to binding to the promoter of tumor suppressor gene CCDC8 and suppresses CCDC8 expression. CCDC8 dysregulation is responsible for G9a-mediated radioresistance of A549/IR cell and XWLC-05/IR cell. Conclusion G9a and H3K9me3 contribute to the lung cancer radioresistance via modulating CCDC8 expression.

Epigenetic mechanisms regulate sex differences in cardiac reparative functions of bone marrow progenitor cells

“…8 ). G9a/Ehmt2 histone methyltransferase (HMT) has been well reported to be involved in the catalysis of H3K9 di and tri-methylation in vitro and in vivo 65 – 67 . We show that inhibition of G9a using BIX-01294 as well as by G9a-specific siRNA resulted in the upregulation of CCL3 in all EPCs.…”

Euchromatic histone lysine methyltransferase 2 facilitates radioresistance in prostate cancer by repressing endoplasmic reticulum protein 29 transcription

“…The methyltransferase inhibitor CM‐272 repressed the activity of EHMT2, resulting in a clear reduction in prostate cancer cell survival 28 . It has been documented that EHMT2 catalyzes H3K9me3 in the promoter of tumor suppressor gene CCDC8, and downregulation of EHMT2 increases the radiosensitivity and curbs the invasive capability of radioresistant lung cancer cells by increasing CCDC8 expression 29 . Moreover, reactive oxygen species (ROS) can modify H3K9 methylation in the E‐cadherin promoter via EHMT2 and promote radiation‐induced epithelial‐mesenchymal transition in lung cancer cells 30 .…”

“…increasing CCDC8 expression. 29 Moreover, reactive oxygen species (ROS) can modify H3K9 methylation in the E-cadherin promoter via EHMT2 and promote radiation-induced epithelial-mesenchymal transition in lung cancer cells. 30 However, there have been no studies on the up-or downstream signals of EHMT2 in the response of prostate cancer cells to radiation.…”

The Role and Mechanism of the Histone Methyltransferase G9a in Tumors: Update

“…G9a-controlled H3K9me3 interacts with the promoter of the tumor suppressor gene coiled-coil domain containing 8 (CCDC8) and suppresses its expression, promoting radio-resistance in lung cancer cells. 26 Nagaraja et al indicate that in epithelial cells, X-ray radiation can alter the global histone methylation levels, mediating the expression of radiation-induced EMT markers in lung cancer cells through the ROS/Snail/G9a pathway. 27 …”