泛素特異性胜肽酶二十四在肺癌生長，惡化與腫瘤相關微環境中所扮演的角色

王毅昌

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泛素特異性胜肽酶二十四在肺癌生長，惡化與腫瘤相關微環境中所扮演的角色

The role of USP24 in lung cancer proliferation, malignancy, and tumor-associated microenvironment

王毅昌 , Ph.D　　Advisor：洪建中　　Co-advisor ：張文昌

英文

肺癌；泛素化；泛素特異性胜肽酶24 ； lung cancer ； ubiquitination ； USP24

Abstract │ Reference (113) │ Altmetrics

Abstract 〈TOP〉

泛素化 (ubiquitination) 為可逆的轉譯後修飾機制，可藉由影響蛋白質的穩定性、親和性或細胞內位置而影響細胞的功能。過去的研究多著重在參與泛素化過程的E3泛素連結酶 (E3 ligase)，且已證實E3泛素連結酶的變異與癌症發生有關。然而關於移除泛素化的酵素 (deubiquitinating enzyme) 在近幾年才受到重視，因此許多去泛素化酵素與癌症的關聯性仍不明確。本篇研究目的在於釐清泛素特異性胜肽酶24 (ubiquitin specific peptidase 24, USP24) 在肺癌發展中所扮演的角色。首先，我們發現在肺癌早期，上皮生長因子接受器 (epidermal growth factor receptor, EGFR) 路徑活化會導致USP24被磷酸化並降低USP24的表現，進一步導致USP24受質Bax、p300的泛素化增加而被降解，同時減少Ku70的乙醯化 (acetylation) 而抑制癌細胞的細胞凋亡。除了Bax、p300以外，我們也發現USP24的減少會降低USP24的受質E2F4與securin的表現量，並進一步促進細胞週期G1/S的轉化 (G1/S transition) 與分裂週期中的中/後期轉化 (metaphase/anaphase transition)， 因此加速癌細胞生長。此外，當USP24表現量降低時，癌細胞可藉由失去E2F4的轉錄抑制作用而過度表現下游調控DNA修復的基因RAD51，或可能藉由增加DNA甲基轉移酵素 (DNA methyltransferase) DNMT1的表現，進一步抑制轉錄因子RBL2/p130的表現而增加RAD54L此調控DNA修復的基因，最終使癌細胞對Camptothecin (CPT) 此抗癌藥物產生抗藥性。在肺癌晚期，我們發現USP24本身的單核甘酸多型性 (single nucleotide polymorphism, SNP) 與RNA編輯 (RNA editing) 可經由增加USP24 RNA穩定度而導致USP24表現增加，穩定MDM2此E3 ligase的蛋白質穩定度，進一步抑制組織蛋白甲基轉移酶Suv39H1所造成的基因靜默 (silencing) 而促進癌細胞轉移。除了在癌細胞本身的研究外，我們也發現與腫瘤相關的巨噬細胞 (tumor-associated macrophages, TAMs) M2分化過程中， USP24表現量的增加可能會經由調控p300促進M2巨噬細胞中NF-B的表現，最後刺激IL-6的表現與分泌，或是藉由減少肺癌細胞本身IL-6啟動子 (promoter) 上的甲基化 (methylation) 修飾而促進IL-6的表現與分泌，進一步加速癌細胞的轉移。根據本篇研究，我們證實在肺癌中USP24不論在促進癌細胞生長、抗藥性的產生、癌細胞轉移與腫瘤相關微環境 (tumor-associated microenvironment) 中都扮演重要的角色，顯示USP24有成為一個診斷與治療標的潛力。

Parallel Abstract 〈TOP〉

Ubiquitin is a critical modifier that regulates the degradation and function of its target proteins via post-translational modification. Numerous studies have found that E3 ligases, which can join ubiquitin molecules and substrates with covalent bonds, are related with cancer formation; however, the relation between deubiquitinating enzymes and cancer is still unclear. In this study, we elucidated multiple roles of a novel deubiquitinating enzyme, ubiquitin-specific peptidase 24 (USP24), in lung cancer progression. First, we found that activation of EGFR signaling pathway caused USP24 phosphorylation and downregulation, resulting in the degradation of its substrates, Bax and p300, and the decrease of Ku70 acetylation, therefore attenuating cancer cell apoptosis. Second, we found other substrates of USP24, such as E2F4 and securin, were also decreased after USP24 downregulation, resulting in the acceleration of cancer cell proliferation through increasing G1/S transition and metaphase/anaphase transition. Moreover, the downregulated E2F4 led to the upregulation of RAD51, which is a crucial gene for DNA damage repair, and led to CPT resistance. Downregulated USP24-induced DNMT1 (DNA methyltransferases 1) upregulation might also involved in DNA damage repair through increasing RAD54L expression. In the late stage of lung cancer, we found that single nucleotide polymorphism (SNP) and RNA editing of USP24 increased USP24 level by increasing its RNA stability. Upregulated USP24 could promote metastasis through stabilizing E3 ligase MDM2, resulting in the decrease of methyltransferase Suv39h1 and decrease of histone H3 lysine-9 methylation. We also found that USP24 was upregulated when monocyte differentiates into tumor-associated M2 macrophages. Increased USP24 might induce interleukin 6 (IL-6) expressions and secretion in tumor-associated microenvironment through regulating p300 and NF-B expression or IL-6 promoter methylation and promote cancer metastasis. Based on these results, we have proved that USP24 plays important roles in cancer cell apoptosis, proliferation, drug resistance, metastasis, and tumor associated microenvironment. By elucidating these detail mechanisms, we hope we can provide new diagnostic and therapeutic strategies for lung cancer treatment.

Reference ( 113 ) 〈TOP〉

Al Mohammad, B., Brennan, P. C., & Mello-Thoms, C. (2017). A review of lung cancer screening and the role of computer-aided detection. Clin Radiol, 72(6), 433-442. doi: 10.1016/j.crad.2017.01.002
Amsel, A. D., Rathaus, M., Kronman, N., & Cohen, H. Y. (2008). Regulation of the proapoptotic factor Bax by Ku70-dependent deubiquitylation. Proc Natl Acad Sci U S A, 105(13), 5117-5122. doi: 10.1073/pnas.0706700105
Araujo, A., Ribeiro, R., Azevedo, I., Coelho, A., Soares, M., Sousa, B., . . . Scagliotti, G. V. (2007). Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer--a review of the literature. Oncologist, 12(2), 201-210. doi: 10.1634/theoncologist.12-2-201
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