NEIL3 Regulates Paclitaxel Resistance Via P300-Mediated Modification of H3K27ac in TNBC
Objectives: To explored the function of NEIL3 in the Triple-negative breast cancer (TNBC) with PTX resistance. And the relationship between the NEIL3 and H3K27ac, and the underlying mechanisms were also detected.
Methods: The NEIL3 expression in the humaneTNBC and cells with PTX resistance was determined by qPCR and west- ern blot. The cell viability was detected by CCK-8. The NEIL3 was silenced or overexpressed to show its function on the cell viability, cell invasion,mitochondrial respiration (cellular oxygen consumption rates,OCR). The interaction between the NEIL3 and P300 was showed by Luciferase assay. And the chromatin immunoprecipitation assays were used to show the relationship between NEIL3 H3K27ac and P300.
Results: NEIL3 expression was low in the PTX resistance TNBC cancer tissue and MDA-MB-231, BT-20 cells. When the NEIL3 was silenced, the OCR, PTX resistance and invasion was promoted in MDA-MB-231 and BT-20 cells. While the NEIL3 overexpressed, the PTX resistance, invasion and OCR was inhibited. Silenced P300 can promote the interaction between the NEIL3 promoter and H3K27ac, leading to increase NEIL3 expression.
Conclusions: NEIL3 expression was regulated by P300 modifications of H3K27ac. P300 recruits to the promoter region of NEIL3 through acetylation of H3K27ac, synergistically inhibiting the transcription and expression of NEIL3, ultimately inducing the PTX resistance in TNBC.
1. Mehta AK, Cheney EM, Hartl CA, Pantelidou C, Oliwa M, Cas- trillon JA, et al. Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer 2021;2(1):66–82.
2. Afghahi A, Timms KM, Vinayak S, Jensen KC, Kurian AW, Carl-son RW, et al. Tumor BRCA1 reversion mutation arising during neoadjuvant platinum-based chemotherapy in triple-nega- tive breast cancer is associated with therapy resistance. Clin Cancer Res 2017;23(13):3365–70.
3. TangY, Tian W, Zheng S, ZouY, Xie J, Zhang J, et al. Dissection of FOXO1-induced LYPLAL1-DT impeding triple-negative breast cancer progression via mediating hnRNPK/beta-catenin com- plex. Res Wash DC 2023;6:0289.
4. Wu S, Lu J, Zhu H, Wu F, MoY, Xie L, et al. A novel axis of circKI- F4A-miR-637-STAT3 promotes brain metastasis in triple-nega- tive breast cancer. Cancer Lett 2024;581:216508.
5. Kwon WS, RhaSY, Jeung HC, Kim TS, Chung HC. Modulation of HAT activity by the BRCA2 N372H variation is a novel mecha- nism of paclitaxel resistance in breast cancer cell lines. Bio- chem Pharmacol 2017;138:163–73.
6. Blanchard Z, Paul BT, Craft B, ElShamy WM. BRCA1-IRIS inac- tivation overcomes paclitaxel resistance in triple-negative breast cancers. Breast Cancer Res 2015;17(1):5.
7. Stordal B, Davey R. A systematic review of genes involved in the inverse resistance relationship between cisplatin and pa- clitaxel chemotherapy: Role of BRCA1. Curr Cancer Drug Tar- gets 2009;9(3):354–65.
8. Li F, Niu M, Qin K, Guo R, Yi Y, Xu J, et al. FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and pacli- taxel resistance. Oncogene 2023;42(5):339–50.
9. Liu M, Li Y, Zhang C, Zhang Q. Role of aurora kinase B in regu- lating resistance to paclitaxel in breast cancer cells. Hum Cell 2022;35(2):678–93.
10. Dan VM, Raveendran RS, Baby S. Resistance to interven- tion: Paclitaxel in breast cancer. Mini Rev Med Chem 2021;21(10):1237–68.
11. Zhang H, Zheng Y. LPCAT1 is transcriptionally regulated by FOXA1 to promote breast cancer progression and paclitaxel resistance. Oncol Lett 2023;25(4):134.
12. Qiu N, Jin H, Cui L, ZhanYT, Xia HM, Jiang M, et al. IFT20 con- fers paclitaxel resistance by triggering beta-arrestin-1 to modulate ASK1 signaling in breast cancer. Mol Cancer Res 2023;21(3):214–27.
13. Wang Y, Xu L, Shi S, Wu S, Meng R, Chen H, et al. Deficiency of NEIL3 enhances the chemotherapy resistance of prostate cancer. IntJ Mol Sci 2021;22(8):4098.
14. Wang Q, LiZ, Yang J, Peng S, Zhou Q, Yao K, et al. Loss of NEIL3 activates radiotherapy resistance in the progression of pros- tate cancer. Cancer Biol Med. 2021;19(8):1193–210.
15. Takao M, OohataY, Kitadokoro K, Kobayashi K, IwaiS, YasuiA, et al. Human Nei-like protein NEIL3 has AP lyase activity specific for single-stranded DNA and confers oxidative stress resistance in Escherichia coli mutant. Genes Cells 2009;14(2):261–70.
16. Lin H, Hu S, Li Y, Li S, Teng D, Yang Y, et al. H3K27ac-activated lncRNA NUTM2A-AS1 facilitates the progression of colorectal cancer cells via microRNA-126-5p/FAM3C axis. Curr Cancer Drug Targets 2024;24(12):1222-34.
17. Kuang R, Xu Z, Zhou H, Zhang Z, Peng H, Wang D, et al. H3K27ac modification and transcription characteristics of adi- pose and muscle tissues in Chuxiang black pig. Anim Genet 2024; 55(2):217-229
18. Xiang H, Tang H, He Q, Sun J, Yang Y, Kong L, et al. NDUFA8 is transcriptionally regulated by EP300/H3K27ac and promotes mitochondrial respiration to support proliferation and inhibit apoptosis in cervical cancer. Biochem Biophys Res Commun 2024;693:149374.
19. Kozlenkov A, Vadukapuram R, Zhou P, Fam P, Wegner M, Dracheva S. Novel method of isolating nuclei of human oligo- dendrocyte precursor cells reveals substantial developmental changes in gene expression and H3K27ac histone modifica- tion. Glia 2024;72(1):69–89.
20. Jiang T, Zhou ZM, Ling ZQ, Zhang Q, Wu ZZ, Yang JW, et al. Pig H3K4me3, H3K27ac, and gene expression profiles reveal re- productive tissue-specific activity of transposable elements. Zool Res 2024;45(1):138–51.
21. Lin S, Wang C, Li Z, Qiu X, et al. Distinct H3K27me3 and H3K27ac modifications in neural tube defects induced by benzo[a]pyrene. Brain Sci 2023;13(2):334.
22. Kim YW, Kang J, Kim A. Hematopoietic/erythroid enhancers activate nearby target genes by extending histone H3K27ac and transcribing intergenic RNA. FASEB J 2023;37(4):e22870.
23. Wu Y, Tirichine L. Chromosome-wide distribution and char- acterization of H3K36me3 and H3K27ac in the marine model diatom Phaeodactylum tricornutum. Plants Basel 2023;12(15):2852.
24. Guo H, Zhou M, Zhang G, He L, Yan C, Wan M, et al. Develop- ment of homozygous tetraploid potato and whole genome doubling-induced the enrichment of H3K27ac and potentially enhanced resistance to cold-induced sweetening in tubers. Hortic Res. 2023;10(3):uhad017.
25. Mahmood SR, Said NH, Gunsalus KC, Percipalle P. Beta-actin mediated H3K27ac changes demonstrate the link between compartment switching and enhancer-dependent transcrip- tional regulation. Genome Biol 2023;24(1):18.
26. Zhao T, Zhang T, Zhang Y, Zhou B, Lu X. Paclitaxel resistance modulated by the interaction between TRPS1 and AF178030.2 in triple-negative breast cancer. Evid Based Complement Al- ternat Med 2022;2022:6019975.
27. HackingSM, Karam J, Singh K, Uzun EDG, Brickman A, Yakirev- ich, et al. Whole slide image features predict pathologic com-plete response and poor clinical outcomes in triple-negative breast cancer. Pathol Res Pract 2023;246:154476.
28. JiY, LiJ, Xiao S, Kwan HY, Bian Z, Chu CC. Optimization of ami- no acid-based poly(ester urea urethane) nanoparticles for the systemic delivery of gambogic acid for treating triple-nega- tive breast cancer. Biomater Sci 2023;11(12):4370–84.
29. Gehre S, Meyer F, SengedorjA, Grottker F, ReichardtCM, Alomo J, et al. Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint mol- ecules after hypofractionated irradiation of MDA-MB-231 tri- ple-negative breast cancer cells. Front Oncol 2023;13:981239.
30. Zhang S, Liu X, Chen W, Zhang K, Wu Q, Wei Y. Targeting TAF1 with BAY-299 induces antitumor immunity in triple-negative breast cancer. Biochem Biophys Res Commun 2023;665:55–63.
31. Sanchez-Gonzalez C, Formentini L. An optimized protocol for coupling oxygen consumption rates with beta-oxidation in isolated mitochondria from mouse soleus. STAR Protoc 2021;2(3):100735.
32. Berry KLE, Hess S, Clark TD, Wenger AS, Hoogenboom, Negri AP. Effects of suspended coal particles on gill structure and oxygen consumption rates in a coral reef fish. Mar Pollut Bull 2021;169:112459.
33. Wu J, Gong L, Li Y, LiuT, Sun R, Jia K, et al. SGK1 aggravates id- iopathic pulmonary fibrosis by triggering H3K27ac-mediated macrophage reprogramming and disturbing immune ho- meostasis. IntJ Biol Sci 2024;20(3):968–86.
34. Shaukat A, Bakhtiari MH, Chaudhry DS, Khan MHF, Akhtar J, Abro AH, et al. Mask exhibits trxG-like behavior and associates with H3K27ac marked chromatin. Dev Biol 2024;505:130–40.
35. Zhuang S, Lu W, Shen L, Huang Z, Zhang X, Zhang Y. RNAS- EH1-AS1 induced by H3K27ac stabilizes ANXA2 mRNA to pro- mote the progression of colorectal cancer through recruiting BUD13. Neoplasma 2023;70(5):597–609.
36. Ma Y, Zheng W. Retraction note: H3K27ac-induced lncRNA PAXIP1-AS1 promotes cell proliferation, migration, EMT, and apoptosis in ovarian cancer by targeting miR-6744-5p/PCBP2 axis. J Ovarian Res 2023;16(1):239.
37. Zhu Y, Zhou Z, Huang T, Zhang Z, Li W, Ling Z, et al. Mapping and analysis of a spatiotemporal H3K27ac and gene expres- sion spectrum in pigs. Sci China Life Sci 2022;65(8):1517–34.
38. Zhao PW, Cui JX, Wang XM. Upregulation of p300 in paclitaxel- resistant TNBC: Implications for cell proliferation via the PCK1/ AMPK axis. Pharmacogenomics J 2024;24(2):5.