The multilayered control of acetylation during adenovirus-based immunotherapy of cancer

Abstract

Adenoviruses are highly immunogenic agents that have shown promise first as gene delivery vectors and later as oncolytic viruses. Currently, oncolytic adenoviruses are featured in over 30% of cancer virotherapy clinical trials. Due to their effective cellular uptake and hijack of cellular machinery, replication-competent adenoviruses are promising therapeutic agents for treating a wide range of tumors. Adenoviral influence on host cell acetylome regulation has regained attention, as these viruses redirect or suppress acetylation during replication, making them potentially desirable therapeutic agents for cancers driven by epigenetic modifications. In this review, we aim to cover the viral processes influencing the acetylome of the host genome. In addition, we shall discuss the effect of differential acetylation on the antiviral defense mounted by the host immune system. Lastly, we will discuss the opportunities for combining acetylation modifiers with oncolytic adenoviruses to improve further outcomes for patients treated with viroimmunotherapy.

Keywords: E1A; MT: Regular Issue; acetylation; adenoviral proteins; cancer; epigenome; oncolytic viruses; p300.

Graphical abstract

Figure 1

Adenovirus-induced alterations in acetylation and their impact on gene expression (A) E1A protein redirects p300-mediated acetylation on the host genome to facilitate viral replication. (B) E1A disrupts the p300-HDAC3-YY1 complex, promoting c-Myc transcription. (C) E1A recruits acetyltransferases from the TRRAP complex, enhancing cyclin A and cdc6 expression. (D) E1A-p300 interaction leads to histone acetylation on adenoviral DNA in “adenosomes,” facilitating transcription. (E) E1A-bound GCN5 represses adenoviral gene transcription. (F) E1A interacts with HBO1 (MYST family) to acetylate H3K14 on the viral genome, enhancing viral gene expression. This figure was created with BioRender.com.

Figure 2

Adenovirus-induced alterations in acetylation and their effects on the proteome (A) E1A-p300 interaction inhibits p53 acetylation, reducing its stability and promoting E1B-55K-mediated proteasomal degradation. (B) E1A forms a complex with p300 and pRb, leading to pRb acetylation, decreased pRb phosphorylation, and enhanced pRb-mdm2 binding. (C) Acetylation of E1A by various acetyltransferases modulates its CtBP binding and transcriptional repression activities. (D) Acetylated E1A cannot bind to importin α3, preventing its nuclear translocation and subsequent influence on gene expression. This figure was created with BioRender.com.