DDI2 promotes tumor metastasis and resists antineoplastic drugs-induced apoptosis in colorectal cancer
Tóm tắt
The normal colorectal mucosa undergoes precancerous lesions that can develop over time into colorectal cancer (CRC). In the stage of precancerous lesions, DNA replication stress may lead to genome instability. We have performed whole-exome sequencing on genomic DNA obtained from three cases of CRC tissues and identified a novel frameshift mutation of DNA damage inducible 1 homolog 2 gene (DDI2, c. 854 del T). To date, there is no direct evidence that DDI2 is involved in the carcinogenesis of CRC. In this study, we demonstrated that DDI2 is upregulated in the early stage of CRC based on clinical samples and public databases. We also found that 5FU, a standard chemotherapeutic agent for CRC treatment, increased DDI2 mRNA levels in a dose-dependent manner. Depression of DDI2 inhibited CRC cell proliferation, migration and invasion both in vitro and in vivo. Transcriptome sequencing revealed that DDI2 was involved in the mitogen-activated protein kinase (MAPK) pathway. Furthermore, DDI2 resists a MAPK kinase (MEK) inhibitor (trametinib) and a PolyADP-ribose polymerase 1 (PARP1) inhibitor (talazoparib) induced apoptosis in CRC cells. Thus, our results indicate that DDI2 may play a vital role in the carcinogenesis of CRC and could serve as a promising therapeutic target for CRC.
Tài liệu tham khảo
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. Cancer J Clin 69(1):7–34
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532
Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319(5868):1352–1355
Macheret M, Halazonetis TD (2015) DNA replication stress as a hallmark of cancer. Annu Rev Pathol 10:425–448
Kottemann MC, Conti BA, Lach FP, Smogorzewska A (2018) Removal of RTF2 from stalled replisomes promotes maintenance of genome integrity. Mol Cell 69(1):24–35
Koizumi S, Irie T, Hirayama S, Sakurai Y, Yashiroda H, Naguro I, Ichijo H, Hamazaki J, Murata S (2016) The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction. Elife 5:e18357
Dirac-Svejstrup AB, Walker J, Faull P, Encheva V, Akimov V, Puglia M, Perkins D, Kümper S, Hunjan SS, Blagoev B (2020) DDI2 is a ubiquitin-directed endoprotease responsible for cleavage of transcription factor NRF1. Mol Cell 79(2):332–341-e337
Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ (2010) Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell 38(1):17–28
Gu Y, Wang X, Wang Y, Li J, Yu F-x (2020) HIV protease inhibitor Nelfinavir targets human DDI2 and potentiates proteasome inhibitor-based chemotherapy. bioRxiv. https://doi.org/10.1101/2020.05.03.075572
Northrop A, Vangala JR, Feygin A, Radhakrishnan SK (2020) Disabling the protease DDI2 attenuates the transcriptional activity of NRF1 and potentiates proteasome inhibitor cytotoxicity. Int J Mol Sci 21(1):327
Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4(12):937–947
Ryan MB, Der CJ, Wang-Gillam A, Cox AD (2015) Targeting RAS-mutant cancers: is ERK the key? Trends Cancer 1(3):183–198
Sun C, Fang Y, Yin J, Chen J, Ju Z, Zhang D, Chen X, Vellano CP, Jeong KJ, Ng PK-S (2017) Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. Sci Transl Med 9(392):eaal5148
Chaudhuri AR, Nussenzweig A (2017) The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 18(10):610–621
Cohen-Armon M (2007) PARP-1 activation in the ERK signaling pathway. Trends Pharmacol Sci 28(11):556–560
Visochek L, Grigoryan G, Kalal A, Milshtein-Parush H, Gazit N, Slutsky I, Yeheskel A, Shainberg A, Castiel A, Seger R (2016) A PARP1-ERK2 synergism is required for the induction of LTP. Sci Rep 6(1):1–16
Cohen-Armon M, Yeheskel A, Pascal JM (2019) Signal-induced PARP1-Erk synergism mediates IEG expression. Signal Transduct Target therapy 4(1):1–8
Chen E, Yang F, He H, Li Q, Zhang W, Xing J, Zhu Z, Jiang J, Wang H, Zhao X (2018) Alteration of tumor suppressor BMP5 in sporadic colorectal cancer: a genomic and transcriptomic profiling based study. Mol Cancer 17(1):1–13
Lei L, Zhao X, Liu S, Cao Q, Yan B, Yang J (2019) MicroRNA-3607 inhibits the tumorigenesis of colorectal cancer by targeting DDI2 and regulating the DNA damage repair pathway. Apoptosis 24(7–8):662–672
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249
Sobrero AF, Aschele C, Bertino JR (1997) Fluorouracil in colorectal cancer–a tale of two drugs: implications for biochemical modulation. J Clin Oncol 15(1):368–381
Hagenkort A, Paulin CB, Desroses M, Sarno A, Wiita E, Mortusewicz O, Koolmeister T, Loseva O, Jemth A-S, Almlöf I (2017) dUTPase inhibition augments replication defects of 5-Fluorouracil. Oncotarget 8(14):23713
Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973–981
Beckman RA, Loeb LA (2006) Efficiency of carcinogenesis with and without a mutator mutation. Proc Natl Acad Sci 103(38):14140–14145
Sharp SP, Malizia RA, Walrath T, D’Souza SS, Booth CJ, Kartchner BJ, Lee EC, Stain SC, O’Connor W Jr (2018) DNA damage response genes mark the early transition from colitis to neoplasia in colitis-associated colon cancer. Gene 677:299–307
Ingraham HA, Tseng B, Goulian M (1982) Nucleotide levels and incorporation of 5-fluorouracil and uracil into DNA of cells treated with 5-fluorodeoxyuridine. Mol Pharmacol 21(1):211–216
Glazer RI, Lloyd LS (1982) Association of cell lethality with incorporation of 5-fluorouracil and 5-fluorouridine into nuclear RNA in human colon carcinoma cells in culture. Mol Pharmacol 21(2):468–473
Waldner MJ, Neurath MF (2012) Targeting the VEGF signaling pathway in cancer therapy. Expert Opin Ther Targets 16(1):5–13
Gu Y, Wang X, Wang Y, Wang Y, Li J, Yu F-X (2020) Nelfinavir inhibits human DDI2 and potentiates cytotoxicity of proteasome inhibitors. Cell Signal 75:109775