肺癌在全球病例中患病率和致死率一直居高不下，主要歸因於肺癌早期病徵的不明顯，病患往往在中晚期才確診導致治療困難。其中最棘手的就是在治療過程中產生的抗藥性。因此，進一步的了解肺癌進程以及抗藥性的機制在藥物開發中至關重要。過去實驗室致力於研究泛素特異性胜肽酶24（USP24），並且揭示USP24會在肺癌晚期積累、誘導腫瘤轉移、協助抵抗藥物壓力等以促進肺癌惡化、產生抗藥性。而先前的研究也表明USP24與 DNA修復的活性、分離缺陷有關，這暗示了USP24在肺癌進展中可能誘導基因組不穩定，從而誘發癌症基因異質性，最終導致抗藥性的發生。因此本研究想要闡明在肺癌治療期間USP24如何影響基因組的完整性去促進抗藥性的產生。在本研究中發現了USP24會負調控DNA損傷修復活性、下調DNA損傷反應的相關基因，還會抑制有絲分裂中的細胞自噬進而影響細胞分裂及細胞週期的進展，並且證明了這些影響會導致細胞更容易累積變異、且發現在紫杉醇治療下擁有較高的腫瘤突變負擔。然而USP24下調誘導細胞自噬的機制需要更多證據支持，未來將會持續研究並試圖闡明。希望藉此更加了解USP24在基因組不穩定中的作用和分子機制，這對於對抗癌症抗藥性十分重要。

The mortality rate of lung cancer worldwide remains high, mainly due to the fewer symptoms and the difficulty of treatment. Moreover, despite the continuous progress and diversification of related treatment methods, many patients still suffer from drug resistance during the treatment process. Thus, understanding the mechanism and resistance of cancer is essential for drug development. Our previous study about ubiquitin-specific peptidase 24 (USP24) indicated that USP24 accumulated in the late stage of lung cancer promoted metastasis and drug resistance. Our preliminary results also revealed that USP24 negatively regulates DNA repair activity and found that overexpression of GFP-USP24 induced cell cycle arrested anaphase, implying that USP24 in cancer late stage may induce genomic instability to result in cancer genetic heterogeneity, leading to cancer malignancy finally. To elucidate the detailed mechanism of how USP24 affects genomic integrity and drug resistance during cancer therapy. First, this study found that USP24-knockdown A549 treated with Taxol accumulated mutations much slower than the control group and drug resistant cell line through whole genome sequencing. This result indicated that USP24 promotes drug resistance might be due to an increase in the mutation rate, leading to genomic instability. Second, this study showed that USP24 negatively regulates DNA damage repair by checking γH2AX foci, a DNA damage response (DDR) biomarker. Moreover, many genes related to DNA damage response were upregulated under the knockdown of USP24 by RNA-seq. Third, this study found that USP24 may decrease the structure variant (SV) of chromosomes and more segregation defects like anaphase chromatin bridges under GFP-USP24 overexpressed cells and more cells arrested in the G2 phase and towards apoptosis or aneuploid cell. Finally, this study also found that autophagy was induced and promoted mitotic progression, but autophagy will not be induced in drug resistance cell line T24 during mitosis. Blocking the autophagy by Bafilomycin A1 led to cell cycle arrest and detected segregation defects. Taken together, USP24 downregulation increase DNA repair and may induce autophagy during mitosis, thereby stabilizes genomic stability. The mechanism of inducing autophagy by USP24 downregulation is not clear enough and will be elucidated in the future. Hope we can delineate the role and molecular of USP24 in genomic instability, which is critical for cancer progression.

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