MSc (Pharmacy) Jonna Tenhunen investigated in her doctoral thesis the regulation of sirtuins. Sirtuins are possible targets for drugs in many diseases such as cancer, neurological diseases, and metabolic disorders. The results of the thesis can be used in developing treatments for sirtuin-related diseases. The public examination will be held at Kuopio Campus and online on 5th of December 2020.
Sirtuins are proteins that control several cellular functions such as cell division, metabolism and gene expression. There are seven human sirtuins, and Tenhunen concentrated especially on investigating SIRT6 and its modulators in her thesis. The function of SIRT6 should be either activated or inhibited depending on the disease in question. For example, in cancer SIRT6, as well as its relative, SIRT1, can either inhibit or activate the cellular processes that are important for cancer. For this reason, both activators and inhibitors for sirtuins should be developed.
The first known SIRT6 modulators were natural fatty acids. In the thesis, other SIRT6-modulating natural compounds were discovered. Anthocyanidins, the colour substances in bilberry and cranberry, activated SIRT6. Catechins, that are present in green tea, were SIRT6 inhibitors. Some of the tested compounds, such as quercetin occurring in red onions and lingonberry, could either inhibit or activate SIRT6 depending on the amount that was used. Some synthetic derivatives of these natural compounds were also SIRT6 inhibitors and activators. The most effective activators showed anticancer effects in breast and colon cancer cells.
As these natural compounds affect the activity of other proteins and are quite unstable, they cannot be used as drugs as such. However, in her thesis Tenhunen could use these SIRT6 modulators to investigate the possible SIRT6 binding sites of the modulators with computational methods. The knowledge about the binding sites and their properties can aid in the further development of SIRT6 modulators.
As it has been challenging to discover and develop compounds that would activate sirtuins, methods to increase cellular sirtuin amount and therefore activity was investigated in the thesis. One tool to affect the sirtuin amount could be BET inhibitors. They are compounds that regulate cellular functions, suppress cancer growth, and affect the same cancer-related processes as sirtuins. Previously BET inhibitors had been reported to regulate SIRT1 levels in different cancer cells. In her thesis Tenhunen investigated this BET inhibitor-related effect by exposing breast cancer cells to three different BET inhibitors. Both hormone dependent and independent breast cancer cells were used. The results indicated, that BET inhibitors could be used not only to increase but also to decrease the amount of SIRT1 in cells. However, the results were inhibitor- and cell type-dependent. This observation implies that it would be important to evaluate the effects of BET inhibitors in different cells individually.
All in all, the result presented in the thesis provide useful information for the further development of sirtuin modulators.
The doctoral thesis of MSc (Pharmacy) Jonna Tenhunen entitled Exploring SIRT6 modulators and an indirect approach to regulate sirtuin activity will be examined at the Faculty of Health Sciences at the University of Eastern Finland. The opponent of the public examination will be professor Outi Salo-Ahen (Åbo Akademi), and the custos will be docent Maija Lahtela-Kakkonen (University of Eastern Finland). The public examination will be held in English.
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Tenhunen, Jonna. Exploring SIRT6 modulators and an indirect approach to regulate sirtuin activity
