Ubiquitin-conjugating enzyme E2 B regulates the ubiquitination of O6-methylguanine-DNA methyltransferase and BCNU sensitivity in human nasopharyngeal carcinoma cells

Shih Han Hsu, Shang Hung Chen, Ching Chuan Kuo, Jang Yang Chang

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes the alkyl groups from the O6 position of guanine and is then degraded via ubiquitin-mediated degradation. Previous studies indicated that 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) facilitates the ubiquitination and degradation of MGMT in several types of cancer cells. However, the underlying mechanism of MGMT ubiquitination remains unclear. In this study, we demonstrated for the first time that ubiquitin-conjugating enzyme E2 B (UBE2B) is a novel regulator of MGMT ubiquitination mediated by BCNU in nasopharyngeal carcinoma (NPC) cells. The E3 ubiquitin ligase RAD18, a partner of UBE2B, is also involved in BCNU-mediated MGMT ubiquitination. Overexpression/knockdown of UBE2B enhanced/reduced BCNU-mediated MGMT ubiquitination. Surprisingly, UBE2B knockdown significantly increased BCNU cytotoxicity in NPC cells. Therefore, loss of UBE2B seems to disrupt ubiquitin-mediated degradation of alkylated MGMT. We found that UBE2B knockdown reduced MGMT activity, suggesting that loss of UBE2B leads to the accumulation of deactivated MGMT and suppresses MGMT protein turnover in BCNU-treated cells. These findings indicate that UBE2B modulates sensitivity to BCNU in NPC cells by regulating MGMT ubiquitination.

Original languageEnglish
Pages (from-to)327-338
Number of pages12
JournalBiochemical Pharmacology
Volume158
DOIs
Publication statusPublished - 2018 Dec

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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