The interaction of adenovirus E1A with p300 family members modulates cellular gene expression to reduce tumorigenicity

Abstract

The use of adenovirus serotype 2 or 5 (Ad2/5) E1A as therapy for human malignancy requires an understanding of the mechanisms involved in E1A-induced tumor suppression. The prevailing use of E1A in the treatment of human malignancy stresses the non-immunologically mediated, anti-tumorigenic activities of E1A. However, the capacity of E1A to elicit a NK-cell and T-cell anti-tumor immune response and to sensitize tumor cells to lysis by immune effector molecules utilized by NK cells and T cells is also an important component of the anti-tumorigenic activity of E1A. This immune-mediated anti-tumorigenic activity of E1A is not shared by functionally similar viral oncoproteins such as the human papillomavirus type 16 (HPV16) E7 oncoprotein and is dependent on the capacity of E1A to interact with transcriptional coadapter, p300. To further define the molecular mechanisms whereby E1A reduces tumorigenicity, we compared total cellular gene expression in H4 cells, a human fibrosarcoma cell line, to gene expression in H4 cells stably expressing E1A, E7, or mutant forms of E1A that do not bind p300. The expression of E1A, but not E7, in H4 cells modulated the expression of cellular genes that may promote apoptosis, enhance immunogenicity and reduce tumor cell metastasis. The difference in the ability of E1A and E7 to modulate the expression of cellular genes that may influence tumorigenicity was largely attributable to distinct interactions of E1A and E7 with p300. Results of this study will be useful in designing novel strategies to augment the anti-tumorigenic activities of E1A.

Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers

“…Here, we have shown that this effect on p300 is additionally important for NK sensitivity. In this regard, GRHL2 has striking similarities to another p300-inhibitory protein, adenovirus E1a, which also reverses EMT and sensitizes cells to NK killing 24, 26, 52 .…”

Construction of Urothelium-Specific Recombinant Adenovirus and Its Inhibition in Bladder Cancer Cell

“…E1A can sensitize tumor cells in chemotherapy and irradiation. The capacity of E1A to elicit an antitumor immune response and sensitize tumor cells to cytolytic effector molecules is de- pendent on the capacity of E1A to bind the transcriptional co-adaptors p300/CBP [10,11]. The structure of recombinant adenovirus Ad-UPII-E1A was designed to express E1A and 19-kDa E1B proteins of type 5 adenovirus.…”

Overexpression of Adenoviral E1A Sensitizes E1A+Ras-Transformed Cells to the Action of Histone Deacetylase Inhibitors

“…The transforming activity of E1A is determined by its ability to deregulate the cell cycle by binding to and altering the activity of such cellular factors as pRb family proteins [5][6][7] and the cyclin-dependent kinase inhibitors p21Waf1 [8,9] and p27Kip1 [10]. E1A also interacts with chromatin remodeling proteins, including histone acetyltransferase (p300/CBP) [11] and histone deacetylases [12]. This interaction changes the transcription of a number of the genes involved in cell cycle regulation.…”