Scientists have found a gene whose absence may be an important driver for a common form of skin cancer known as squamous cell cancer (SCC), because its presence signals “Stop!” to cell proliferation. The international team found the gene, called Grhl3, is also virtually absent in SCC that arises in other tissues, including head and neck cancers, that often have a poor prognosis. Because drugs that are effective against SCC are already in development for treating other cancers, they hope treatments and prevention therapies for SCC could be offered to patients within five years.

Professor Stephen Jane and Dr Charbel Darido of Monash University’s Department of Medicine at the Alfred Hospital in Prahran, Victoria, Australia, led the team, who write about their findings in the 15 November online issue of Cancer Cell.

Estimates from Australia’s Cancer Council suggest two out of every three Australians will receive a skin cancer diagnosis by the time they reach their 70th birthday, with SCC being one of the most commonly occuring forms.

At present, the only form of treatment is surgical removal, and despite its prevalence, we know little about the underlying genetic and molecular mechanisms of SCC.

In their study, Jane and colleagues discovered that the gene, known as developmental transcription factor Grhl3, a tumor suppressor that also plays a key part in developing skin in the fetus, is absent in adult SCC tumor cells.

Jane told the press:

“Virtually every SCC tumor we looked at had almost undetectable levels of this particular gene, so its absence is a very profound driver of these cancers.”

At first he and his colleagues focused on skin cancer, but when they looked at SCC cells that arise in other tumors, such as neck and head cancers, they found these didn’t have any Grhl3 either. Patients who develop these cancers don’t have many options and the prognosis is often poor.

Using lab mice, they showed that knocking out the gene stops the signal that tells skin cells to stop growing. Without this “stop” signal, the cells keep multiplying, and eventually form a tumor.

In their paper they write how they identify “Grhl3 as a potent tumor suppressor of SCC in mice”, and show that “targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans”, and that deletion of the gene in adult skin causes “loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling”.

When they restored Pten expression, it completely abolished the formation of SCC.

They explain there is evidence that SCC in human skin and head and neck cancers show reduced levels of Grhl3 and Pten, linked to increased expression of the miR-21 signal, which targets both of the tumor suppressors, thus giving the cancer an unobstructed way forward.

“Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC,” they conclude.

Finding this driver of cancer in skin and other organs, is a breakthrough that will hopefully pave the way for speedy development of new prevention and treatment strategies, as Jane explained:

“Our research indicates that drugs already in clinical trials for other cancers may actually be effective in treating SCC – they just need to be applied to skin or head and neck cancers.”

This means that many of the usual hurdles that new drugs have to overcome have already been cleared, “so patients could be reaping the benefits of this research in under five years,” he added.

The researchers hope the path to prevention will also be speedy. There are ways of increasing the expression of the gene that could offer protection from skin cancer, for instance by including a compound that does this in sun-creams.

“The molecules that would increase this expression, are very well validated, so there would be few barriers to applying them in clinical trials,” said Jane.

Written by Catharine Paddock PhD