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Novel Insights on How Prostate Cancer Causes Secondary Tumors; Smad7 Enhances TGF-β-Induced Transcription of c-Jun and HDAC6, Promoting Metastasis of Prostate Cancer Cells; One Amino Acid in Smad7 Proves Key; HDAC6 Inhibitors May Prove Helpful

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 is suggested by new results reported in a just-published study by researchers at Umeå University, Sweden, in collaboration with researchers in Uppsala, Sweden, and Tokyo, Japan. The study was published online on September 3, 2020 in iScience. The open-access article is titled “Smad7 Enhances TGF-β-Induced Transcription of c-Jun and HDAC6 Promoting Invasion of Prostate Cancer Cells.” (Se graphcial summary of article at end. “We can show that one specific amino acid in a signaling molecule plays an important role in mobilizing the cancer cells, and in that way increases the risk of metastases,” says Maréne Landström (photo), MD, PhD, Professor of Pathology, Umeå University. This research has studied the growth factor TGF-β (transforming growth factor beta), which regulates how cells grow and specialize. Previous studies have shown an overproduction of TGF-β in many forms of cancer, 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 and cause life-threatening secondary tumors, 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 feedback. However, Dr. Landström and her research group at Umeå University, and colleagues, have now shown, 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 Lys102 and it is found in Smad7. This amino acid binds to particular gene-regulating functions in DNA to increase production of the gene expression of HDAC6 and c-Jun. This has the effect that cancer cells become more mobile and more prone to form metastases. Researchers have been able to see a clear connection between all these variables and a negative prognosis for prostate cancer.

“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,” says Dr. Landström.

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.

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.

The study also reveals 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 had been thought that Smad7 held the role of inhibitor for TGF beta-Smad2/3 transcriptional activity.

[Umeå news release] [iScience article]

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Graphical summary of article (iScience).