泛素-蛋白酶體系統(Ubiquitin-proteasome system) 是存在於真核細胞中用來代謝蛋白質的一種方式，將要被分解的蛋白質藉由泛素活化酵素(Ubiquitin-activating enzyme, E1)，泛素綴合酶(Ubiquitin-conjugating enzyme, E2)和泛素連接酶(Ubiquitin protein ligase, E3)接上泛素，再經由26S蛋白酶體而降解。我們知道在生長代謝快速的癌細胞此路徑的活性會大幅上升，所以才選擇其作為目標。已知目前在人類中僅有兩種E1酵素，相較於具以多種種類的E2、E3酵素，將其當作標的，更能廣泛研究泛素-蛋白酶體路徑對於癌細胞的影響。我從Human Protein Atlas去分析正常組織和癌細胞中類泛素活化酵素6(Ubiquitin –like Modifier Activating Enzyme 6,UBA6)的表現，發現在癌細胞中其蛋白量上升。我以類泛素活化酵素6作為研究對象利用RNA干擾(RNA interference, RNAi)，在多種癌細胞中(HeLa、MDA-MB-231、PC3)穩定抑制類泛素活化酵素6的表現。根據實驗結果顯示缺乏類泛素活化酵素6的細胞株，相對於對照組從生長的觀察和群落形成的能力有下降的趨勢，從傷口癒合爬行能力測定實驗中也有變慢的情況。透過西方墨點法分析，發現跟生長或爬行的蛋白，例如ERK、Akt等表現量下降，而E-cadherin上升、N-cadherin或vimentin下降。為了更進一步去了解降低此酵素對於癌細胞的影響，因此利用了幾種不同的抗癌藥物依託泊苷(Etoposide) 、2-去氧葡萄糖(2-Deoxyglucose)、每福敏(Metformin)分別對於不同的細胞株處理，發現在2-去氧葡萄糖藥物影響了靜默株形成群落的能力且增加細胞凋亡的數量。根據目前的實驗結果可以得知缺乏類泛素活化酵素6會影響癌細胞的生長及爬行能力，降低細胞的惡性程度。

Ubiquitin-proteasome system is used to degrade cellular protein in eukaryotic cell. Ubiquitin-activating enzyme (E1) uses ATP to active ubiquitin, which is transferred to ubiquitin conjugating enzyme (E2), and ubiquitin-protein ligase (E3) connects E2 with the target protein. Then, ubiquitylated target protein can be degraded by 26S proteasome. We know that the pathway is substantially increased in high growth rate and metabolism of cancer cells, so we chose this way as the target in human cancer therapy. Therefore only two kinds of E1 enzymes are best targets than a diverse of E2s and E3s. Human Protein Atalas show that expression level of Ubiquitin – like Modifier Activating Enzyme 6 (UBA6) in normal tissue and tumor discover that protein expression increases in cancer cell. I have established the stable knockdown UBA6 cancer cell lines by RNAi (RNA interference), including HeLa (cervix cancer), MDA-MB-231 (breast cancer) and PC3 (prostate cancer). The results demonstrate that silencing of UBA6 expression decreases cell growth and migration ability. Analyze some protein such as Akt and ERK in silencing of UBA6 cell lines are found to decrease protein expression. Then EMT related protein finds that E-cadherin is up-regulated and N-cadherin or vimentin is decreased. And then, the glycolytic pathway plays an important role in cancer cells. Therefore, we test the effect of glycolysis in knockdown UBA6 cells by glycolytic inhibitor 2-deoxyglucose (2-DG) and metformin. The result shows that UBA6 knockdown cells have a higher drug sensitivity for 2-DG than metformin. Taken together, decreased UBA6 expression directly attenuates tumor malignancy and increases 2-DG sensitivity, suggesting that provides a new target for anticancer therapy.

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