Researchers at the Indian Institute of Technology (IIT) Kanpur have revealed that a gene (DLX1) involved in the development of the jaws, bones, and interneurons in the brain also has a role in the growth and progression of prostate cancer.
The DLX1 protein has been employed as a urine-based biomarker since it is detected at increased levels in prostate cancer patients. Now, a team of researchers led by Dr. Bushra Ateeq, Professor at IIT Kanpur’s Department of Biological Sciences and Bioengineering, has discovered that the DLX1 protein, which is expressed at higher levels in prostate cancer cells, plays an important role in the tumor’s growth and development, as well as its spread to other organs in the body (metastasis).
The researchers demonstrated in mice a potential therapeutic method for treating humans with DLX1-positive prostate cancer using small compounds as inhibitors.
To begin, the researchers discovered that roughly 60% of prostate cancer tissues contain greater amounts of the DLX1 protein. When the scientists genetically disabled the DLX1 gene, which generates the protein, cancer cells lost their capacity to grow, mature, and spread to other areas of the body.
“We employed mouse models to investigate the function of DLX1 protein in prostate cancer development and metastasis,” explains Sakshi Goel of IIT Kanpur, the paper’s lead author.
To conduct the studies in mice, the researchers first genetically modified prostate cancer cells that produced increased quantities of the DLX1 protein in order to create cells that were unable to make the protein. Two groups of mice were then injected with both kinds of cancer cells. While animals implanted with cancer cells that expressed high amounts of the protein grew large tumours, mice implanted with DLX1-ablated cancer cells developed tiny tumours and had less cancer cells migrate to other organs.
The second experiment on mice looked at cancer cells’ potential to metastasize and develop in bones. “Prostate cancer cells have a proclivity for spreading to the bones.” As a result, we investigated the significance of the DLX1 protein in cancer spread,” Goel explains. They did this by implanting cancer cells into the tibia (bone) of mice that were either DLX1-ablated or expressing greater quantities of the protein. A month following the implant, a CT scan was used to track the growth of the tumour in the tibia. Mice implanted with cancer cells that had high levels of DLX1 had greater bone damage than mice implanted with DLX1-ablated cancer cells. According to Goel, “these data showed the function of DLX1 in prostate tumour progression and bone metastases.”
The androgen receptor has a role in the development of prostate cancer. In addition, around half of all prostate cancers have an abnormal gene, which is the consequence of two genes (TMPRSS2 and ERG) being fused together, resulting in increased levels of ERG protein synthesis.
“Interestingly, investigating the link between these two crucial characteristics found that 96 percent of TMPRSS2-ERG fusion-positive prostate cancer patients also had high levels of DLX1 protein.” According to Prof. Ateeq, “about 70% of individuals with strong androgen receptor signalling also have higher DLX1 protein levels.”
The researchers also discovered that higher levels of DLX1 in prostate cancer cells are caused by both the androgen receptor and the fusion gene product ERG. The researchers switched their focus to finding a strategy to suppress the production of DLX1 protein in cancer cells after figuring out the mechanism behind prostate cancer growth and metastasis to distant organs. They discovered that a certain protein (Bromodomain and extra terminal or BET) helps both the androgen receptor and the ERG function. “We discovered that inhibiting the BET protein with small compounds inhibits both the androgen receptor and the ERG protein’s ability to upregulate DLX1.” As a consequence, DLX1 protein production and tumorigenic potential are lowered,” Goel explains.
BET inhibitors, alone or in conjunction with anti-androgen medications, led to a 70 percent decrease in tumour burden and a reduction in distant metastases in preclinical mouse investigations. “This therapy method may help prostate cancer patients with greater levels of DLX1.” According to Prof. Ateeq, “there are various commercially available diagnostics tests for measuring DLX1 levels, making it reasonably straightforward to identify the individuals who may react to BET inhibitors.”
Source: The Hindu