Genes & Cancer

HDAC8 affects MGMT levels in glioblastoma cell lines via interaction with the proteasome receptor ADRM1

Irene Santos-Barriopedro1, Yixuan Li1, Sonali Bahl1 and Edward Seto1

1 George Washington Cancer Center, Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine & Health Sciences, Washington, DC, USA


Edward Seto, email:

Keywords: HDAC; DNA damage; cell cycle; temozolomide; drug resistance

Received: July 17, 2019 Accepted: September 22, 2019 Published: October 01, 2019


Temozolomide (TMZ) is an alkylating agent chemotherapy drug used as a first-line treatment for glioblastoma multiforme (GBM). O6-methyl-guanine DNA methyltransferase (MGMT) repairs DNA damage induced by TMZ; hence, elevated MGMT levels usually correlate with TMZ resistance. MGMT promoter methylation is a key regulatory mechanism for MGMT expression and is important in overcoming TMZ therapy resistance. To date, little is known about how MGMT expression is regulated beyond promoter methylation. In this work, we show an alternative mechanism by which MGMT levels are regulated independent of its promoter methylation status. We found that inhibition of the histone deacetylase HDAC8 by either HDAC8-specific inhibitor PCI34051 or HDAC8 shRNA decreases MGMT levels in GBM cell lines. Furthermore, the proteasome receptor ADRM1 participates in this MGMT regulation by interacting with HDAC8. Interestingly, this interaction is disrupted by TMZ exclusively in TMZ sensitive cells, suggesting that this MGMT regulatory pathway might be inactivated in TMZ resistant cells. Consequently, HDAC8 inhibition in GBM cell lines increases DNA damage and cell cycle arrest and, eventually, decreases cell viability, likely due to the decrease in MGMT protein levels.

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