Exploring the Role of Acetyl-CoA Acetyltransferase 1 (ACAT 1) as a Putative Substrate of Cereblon (CRBN)

Abstract

Cereblon (CRBN) is a substrate receptor of Cul4 ubiquitin ligase complex and known to be direct target of immunomodulatory drugs (IMiDs). Here I identify ubiquitin-independent activity of CRBN that promotes recruitment of acetyl-coA acetyltransferase 1 (ACAT1). Specific regulation on ACAT1 by CRBN is still unknown, but here I found elevation in ACAT1 protein expression and activity in CRBN-deficient cells, which promotes higher oxidative phosphorylation rate in lung cancer cells. Moreover, disruption of ACAT1 activity in CRBN-deficient background by ACAT1 inhibitor acreoline hydrobromide (AH) shows attenuated non-small lung cancer cell proliferation. These findings reveal mechanistic scheme of how proteasomal regulation on enzymes can bring advantages in cancer cell metabolism, and that both CRBN and ACAT1 status are important for anti-cancer treatment.