LONDON ¿ New cancer therapies and an improved understanding of how viral oncogenes interact with body cells to cause cancer are likely to flow from the discovery that the control of cell division hinges on the presence or absence of acetyl groups on a key cellular protein.
Researchers in Glasgow, UK, say their discovery represents a completely new understanding of how the retinoblastoma tumor-suppressor protein (pRb) regulates cell proliferation.
The finding fits well with a drug discovery strategy already being pursued by the privately owned pharmaceutical company Prolifix, of Abingdon, UK. Prolifix is expected to seek permission shortly for Phase I clinical trials to test drugs in human cancers that alter the acetylation status of tumor cells.
Nicholas La Thangue, Cathcart professor of biochemistry at the University of Glasgow and chief scientific officer of Prolifix, told BioWorld International: ¿pRb is the master regulator of proliferation in the cell ¿ it determines whether or not cells grow and divide. We have now connected this critical cellular protein with the enzymatic process of acetylation, which is a previously unknown mechanism of pRb control.¿
La Thangue and his colleagues report their findings in a paper in Nature Cell Biology titled ¿Acetylation control of the retinoblastoma tumor-suppressor protein.¿
Scrutiny of pRb has been intense, given that it is known to be inactivated or under abnormal control in all human tumor cells. In their paper, La Thangue and his group report a range of experiments showing that pRb is acetylated in normal cells, where growth and division are tightly controlled. They also show that, in tumor cells, pRb acquires tumor-suppressor activity when it becomes acetylated.
When the researchers carried out mutagenesis of the protein, which had the effect of altering the acetylation sites, they found that pRb easily lost tumor-suppressor activity to allow cell division.
La Thangue explained that there are two categories of enzymes in cells that modify the acetylation of pRb: those that add acetyl groups to its lysine residues and those that remove these groups. The protein known as p300 belongs to the former group. Those that carry out the deacetylation reaction are called HDACs.
HDACs already have been identified as good targets for anticancer drugs. ¿Prolifix is developing small-molecule drugs against these HDACs, which appear to be very potent antitumor agents,¿ La Thangue said. Tests in animal models of human tumors suggested, he added, that these compounds can profoundly inhibit tumor growth.
¿We would predict that when we start to treat cells and tumors in vivo with these compounds, we would begin to see high levels of acetylated pRb ¿ the active growth-suppressing state of pRb ¿ because these compounds block the acetyl groups on the protein,¿ La Thangue said.
The paper in Nature Cell Biology also reveals how the adenoviral oncoprotein E1A is likely to exert its oncogenic effect. This oncoprotein has been widely used as a mimic of human oncogenes. When it is added to normal cells in culture, these develop into tumor cells.
¿It had been known for a long time that E1A needs to grab both pRb and p300 when it enters a normal cell in order to act as an oncoprotein, but there was never any explanation for this,¿ La Thangue said. ¿Our studies had shown us that pRb was acetylated, and we knew that p300 could add acetyl groups to pRb. So we wondered if E1A was acting as a catalyst to bring the enzyme, p300, together with the substrate, pRb. We found this was exactly what happened in cells.¿
This begs the question of whether something similar happens when oncoproteins from oncoviruses known to play a role in human cancers ¿ such as human papilloma virus ¿ enter human cells. ¿We know that the E7 oncoprotein from the human papilloma virus requires both pRb and p300 in human cervical cancer cells,¿ La Thangue said. ¿The chances are it does exactly the same to pRb acetylation in cervical carcinoma cells and we are very excited by this possibility.¿
The group also is trying to understand how the cell interprets the acetylation of pRb. La Thangue explained: ¿We know from studies we have done that the acetylation of pRb varies, depending on which acetyl transferase enzyme does the reaction. Our belief is that this provides a code or a signal as to what the pRb protein should do. The type of growth arrest which follows, for example, could be simple growth arrest, or senescence, or apoptosis.¿