並列タイトル等CCNDBP1はATM-CHK2経路を介したDNA損傷に応答する
CCNDBP1 and the ATM–CHK2 pathway
一般注記Background: Since CCNDBP1 is a cyclin D-binding dominantly-negative helix-loop-helix protein that is expressed in various tissues, it is considered a tumor suppressor, as it negatively regulates TGF-β signal-induced cell migration depending on the surrounding condition. When expressed in tumor cells, CCNDBP1 can contribute to the viability of cancer cells by rescuing them from chemotherapy-induced DNA damage. Therefore, this study focused on investigating the function of CCNDBP1, which is directly related to survival from DNA damage and chemoresistance in cancer cells. Methods: Molecular mechanisms of CCNDBP1 related to the recovery from DNA damage were examined in vitro and in vivo, using hepatocellular carcinoma (HCC) cells and tissues obtained from Ccndbp1 knockout mice. X-ray irradiation was then used to induce DNA damage. Subsequently, gene and protein expression changes associated with CCNDBP1's upregulation, downregulation, and irradiation were assessed. Results: As observed, CCNDBP1's overexpression in HCC cells stimulated cell growth and showed resistance to X-ray irradiation. Gene expression analyses of CCNDBP1-overexpressed cells and Ccndbp1 knockout mice revealed that Ccndbp1 inhibitory dependently controlled the expression of Ezh2. However, irradiation Ccndbp1-dependently decreased Ezh2's expression. Further analyses of DNA damage-related protein expressions in vitro and in vivo also showed that Ccndbp1 activated the Atm-Chk2 pathway through the inhibition of Ezh2 expression, thereby accounting the resistance to DNA damage. Conclusions: Our study, therefore, demonstrated that by inhibiting EZH2, CCNDBP1 contributed to the activation of the ATM-CHK2 pathway to alleviate DNA damage, leading to chemoresistance.
Journal of clinical medicine. 2022, 11(3), 851.
新大院博(医)第1038号
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