高糖飲食在現代社會的精緻飲食當中已是難以避免，長期的高糖飲食容易引發代謝性疾病例如糖尿病等。近年來許多研究也指出高糖飲食所引發的代謝失調容易助長腫瘤組織的增生。另外高糖飲食所造成的胰島素抗性和避免細胞凋亡更加造成腫瘤的惡化。高糖飲食也可以透過染色質的修飾調控細胞的表觀遺傳狀態。異染色質蛋白1(Heterochromatin protein1, HP1) 參與異染色質的形成並且可以抑制基因的轉錄與表達。在許多人類癌症上有發現表觀遺傳學失調的現象，文獻也報導異染色質蛋白1在癌症中表現量降低的現象。然而，表觀遺傳的分子調控機制是否在高糖所引發的腫瘤進程扮演重要的角色目前仍不清楚。本研究以果蠅做為高糖飲食的癌症動物，並藉由在Ras/Src 或者Ras/Scrib誘導的腫瘤模式中過度表現或者抑制異染色質蛋白1，來了解異染色質在高糖引發之癌症所扮演的角色。我們發現這兩個腫瘤系統在經過高糖誘導之後都會增加腫瘤動物的生長負擔，造成延緩發育以及降低動物的生存率。除此之外，我們發現高糖飲食可以降低異染色質的表現量，並且造成腫瘤組織的惡化。有趣的是，當我們在兩個高糖誘導腫瘤系統中過度表現或者抑制異染色質蛋白1後，不只能有效地減緩發育延遲、增加整體癌症模式生物的生存率，更有效地造成腫瘤的減小。另外我們也發現，在高糖誘導的腫瘤系統過度表現或者抑制異染色質蛋白1後，可以有效地抑制wingless訊息傳遞路徑，也可以增加腫瘤細胞凋亡。另外，異染色質蛋白1表現量的增加能造成細胞凋亡相關基因的mRNA表現量增加。最後，在染色質免疫沉澱實驗中發現醣質新生相關的基因可以被異染色質蛋白質1所調控。因此，這些證據建議異染色質抑制高糖飲食誘導腫瘤進程。這個研究有助於了解高糖誘導腫瘤的表觀遺傳分子機制，對於高糖飲食所導致的代謝性疾病與癌症治療提供新的治療與解決方向。

High dietary sugar (HDS) not only increases the risk of metabolic diseases but also promotes tumor progression through insulin insensitivity and apoptosis avoidance. Recent evidence has shown that HDS alters epigenome via histone modification. Heterochromatin protein 1(HP1), a major protein in heterochromatin formation, has been found down-regulated in various human cancers. However, the molecular mechanisms by which heterochromatin mediates the progression of tumor via HDS is still unknown. Here, we use Drosophila as an animal model to investigate the role of heterochromatin in HDS-induced tumor progression in vivo. We use two Drosophila tumor systems which are created by carrying the oncogene ras mutation and tumor suppressor gene csk or scrib mutation. We demonstrate that HDS promotes tumor progression in both tumor systems. Interestingly, heterochromatin levels are important for tumor suppression as well as the development and survival of tumor animals. Animals with overexpression and knockdown of HP1 specifically in tumor of both systems show decreased tumor growth and improved pupariation and eclosion rate. Moreover, HDS contributes to heterochromatin reduction and severe tumor progression. Overexpression and knockdown of HP1 decrease wingless signaling and increase apoptosis specifically in tumors. Finally, we identified HP1-regulated genes in apoptosis and glucose metabolism, which may be involved in HDS-induced tumor progression. Taken together, our results suggest that heterochromatin suppresses HDS-induced tumorigenesis. This study may contribute to the prevention and treatment of cancers associated with HDS-induced metabolic disorders.

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