臺灣博碩士論文加值系統

乳癌為我國女性癌症中發生率第 1 位，台灣每年有超過一萬兩千名女性罹患乳癌，在這之中，至少有 12%是高侵略性乳癌，包括三陰性乳癌(Triple negative breast cancer, TNBC)。罹患此類型癌症的患者因而具有早期轉移或是復發的現象，並且治療方式有限。因此了解能控制 TNBC 細胞特性的機轉，是發展根除此類高侵略性乳癌有效治療方式的關鍵。近年研究證據指出代謝重編程對乳癌惡性進展至關重要。丙酮酸激酶PKM2 在癌細胞糖解作用中扮演重要角色。然而，儘管在 PKM2/糖解作用缺失的情況下，TNBC 仍可持續生長，而維持這些乳癌細胞生長的關鍵機制尚未確定。我們最新的發現指出 PKM2/糖解作用的缺乏會激活 TNBC 乳癌細胞趨向脂肪酸氧化 (FAO) 的代謝轉換，從而維持 TNBC 的生長。我們的試驗結果顯示，PKM2 與组蛋白甲基轉移酶 EZH2 在乳癌細胞中會形成相互作用的複合體，共同抑制與 FAO 有關的重要基因表現，包括 SLC16A9。SLC16A9 是轉運肉鹼 (Carnitine) 進細胞的受體，而 Carnitine 是促進 FAO 重要物質。我們發現抑制 PKM2-EZH2 信息傳導，會增加細胞內 Carnitine 的量並促進 FAO，並使乳癌細胞高度依賴 FAO 作用。我們在此研究中得到的結論是，PKM2/EZH2/SLC16A9 的嶄新代謝途徑有機會成為高度臨床相關性的治療生物標記，通過調節 PKM2-EZH2 複合體調控代謝轉換，可以有潛力成為臨床上有效治療 TNBC 的新型療法。

Breast cancer remains to be the most common cancer among women with over 12,000 cases diagnosed annually in Taiwan. Among these cases, at least 12% are highly aggressive breast cancer, including triple-negative breast cancer (TNBC). Patients with this type of cancer often experience early metastasis or recurrence, and treatment options are limited. Therefore, understanding the mechanisms that maintain the TNBC cell growth is crucial for developing effective treatments for this aggressive type of breast cancer. Recent research indicates that metabolic reprogramming is crucial for breast cancer progression. Pyruvate kinase PKM2 has a key role in oxidative glycolysis, a key metabolic pathway in cancer cells. However, TNBC cells continue to grow even loss of PKM2/glycolysis, and the central mechanism that is involved remains unclear. Our latest findings suggest that the blockade/deficiency of PKM2/glycolysis initiates a metabolic switch towards fatty acid β-oxidation (FAO) in TNBC cells to sustain their growth. Our results show that PKM2 forms a chromatin complex with histone methyltransferase EZH2 in TNBC cells, which epigenetically suppresses the expression of genes related to FAO, SLC16A9, a key carnitine transporter that promotes FAO. As a result, inhibiting PKM2/EZH2 prompts TNBC cells to become highly dependent on FAO. In conclusion, our finding implies that the PKM2/EZH2/SLC16A9 regulatory axis has the potential to become a clinically relevant biomarker and a critical therapeutic target in TNBC.

Introduction.........................................................................1
Gap & Hypothesis..............................................................22
Materials and Methods......................................................24
Results................................................................................27
Figures................................................................................30
Discussion...........................................................................39
Conclusion..........................................................................41
References..........................................................................42
Fig 1. Direct interaction of PKM2 and EZH2……………30
Fig 2. Specific domains of PKM2 and EZH2 that mediate PKM2-EZH2 protein-protein interaction…………31
Fig 3. PKM2-EZH2 interaction is critical for nuclear translocation and dimerization of PKM2……..…..34
Fig 4. PKM2-EZH2 complex transcriptionally represses SLC16A9 expression……………………...……..….36
Fig 5. PKM2-EZH2-SLC16A9 regulatory axis clinically correlates with breast cancer subtypes and patient survival………………………….…………………....37

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