An increased awareness on a molecular level of what mechanisms prostate cancer cells use to become mobile and start spreading may in the long run provide new opportunities for treatment of aggressive prostate cancer. This according to a new study by researchers at Umeå University, Sweden, in collaboration with researchers in Uppsala and Tokyo. This research has studied the growth factor TGF-β, or Transforming Growth Factor Beta, which regulates how cells grow and specialise. Previous studies have shown an overproduction of TGF-β in many cancer forms, one being prostate cancer. High levels of TGF-β have proven to be strongly linked with poor prognosis and low survival rates as a consequence of the growth factor stimulating cancer cells to spread in the human body — so-called metastases. TGF-β regulates the expression of the protein Smad7, an active component in the TGF-β signaling chain. In healthy cells, Smad7 can prevent continued TGF-β signaling via negative control over the other positive Smad proteins.
However, the research group can now show, contrary to previous belief, that, in cancer cells, Smad7 can reinforce the development of tumors by regulating the gene expression of HDAC6 and c-Jun. The specific amino acid that has caught the researchers’ attention is called Lysine 102 (K102) and among Smad proteins is found only in Smad7. This amino acid binds to particular gene-regulating functions in DNA to increase the gene expression of two proteins, HDAC6 and c-Jun. This has the effect that cancer cells become more mobile and more prone to form metastases, since these two proteins regulate cell motilitiy and DNA synthesis. Researchers have been able to see a clear connection between all these variables and a negative prognosis for prostate cancer. Clinical trials are now taking place in the UK to find specific HDAC6 inhibitors in patients with solid tumors, which means that treatments using HDAC6 inhibitors can become a complement in the cancer treatment of patients with hard-to-treat forms of disease.
Smad7 has previously been found to be amplified in colorectal carcinoma, and this event is linked to poor prognosis for these patients. Moreover, knockdown of Smad7 expression in a human colorectal carcinoma xenograft model has been shown to reduce tumor growth in vivo (Stolfi et al., 2014), giving further evidence for a tumor-promoting role of Smad7 in colorectal cancer. Future studies can explore the benefit of indicating expressions of Smad7, HDAC6 and c-Jun to enable new and more specific treatments for men with aggressive prostate cancer. Moreover, high expression of HDAC6 is significantly linked to poor prognosis for the patients with prostate cancer, as well as colorectal cancer. The study also shows an entirely new function of Smad7 in the way that it can recruit Smad2 and Smad3 to the place of transcription for these genes. Previously, it has been thought that Smad7 held the role of inhibitor for TGF beta-Smad2/3 transcriptional activity.
Professor Maréne Landström, Umeå University, has concluded: “We can show that one specific amino acid in a signaling molecule plays an important role in mobilising the cancer cells and in that way increase the risk of metastases. The good news is that by using treatment with an HDAC6 inhibitor, we can make prostate cancer cells lose their mobility. In that way, novel opportunities can open up for treatments that reduce the risk of metastases”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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