Inhibition of PRPF19 impairs oncogenesis, radioresistance and DNA damage repair in cervical cancer

Background: Cervical cancer (CC) is one prevalent and lethal gynecological malignancy. Pre-mRNA-processing factor 19 (PRPF19) has been implicated in the progression of multiple cancers and shown to play a role in modulating the DNA damage response. However, the specific regulatory effects of PRPF19 and its associated pathways in the development of CC remain poorly understood. Methods: The protein expressions were inspected through western blot. The survival fraction and the number of colonies were examined through colony formation assay. The fluorescence intensity of gamma-histone H2A family member X (γH2AX) was verified through Immunofluorescence (IF) assay. The cell invasion and migration were tested through Transwell assay. Results: In this study, data from the Gene Expression Profiling Interactive Analysis (GEPIA) and User-friendly Analysis Tool for Cancer Gene Expression Data (UALCAN) online databases were analyzed, and the findings revealed significant overexpression of PRPF19 in cervical squamous cell carcinoma (CESC) tissues. Additionally, we confirmed elevated PRPF19 expression in CC, with the inhibition of PRPF19 increasing the sensitivity of CC cells to X-ray treatment. Furthermore, PRPF19 knockdown enhanced DNA damage following X-ray exposure, as evidenced by increased γH2AX fluorescence intensity and reduced levels of p-DNA-protein kinase (PK) and Rad51 recombinase (Rad51). PRPF19 suppression also inhibited cell migration and invasion. Mechanistically, PRPF19 promoted activation of the Sarcoma (Src)-Yes-associated protein 1 (YAP1) pathway by downregulating p-Src/Src and YAP1 levels. Conclusions: PRPF19 inhibition impairs oncogenesis, reduces radioresistance and disrupts DNA damage repair in CC, partly through modulation of the Src-YAP1 pathway, thereby supporting PRPF19 as one prospective bio-target for CC treatment.

PRPF19; Radioresistance; DNA damage; Cervical cancer; Src-YAP1 pathway

[1] Johnson CA, James D, Marzan A, Armaos M. Cervical cancer: an overview of pathophysiology and management. Seminars in Oncology Nursing. 2019; 35: 166–174.

[2] Tabatabaei FS, Saeedian A, Azimi A, Kolahdouzan K, Esmati E, Maddah Safaei A. Evaluation of survival rate and associated factors in patients with cervical cancer: a retrospective cohort study. Journal of Research in Health Science. 2022; 22: e00552.

[3] Liontos M, Kyriazoglou A, Dimitriadis I, Dimopoulos MA, Bamias A. Systemic therapy in cervical cancer: 30 years in review. Critical Reviews in Oncology/Hematology. 2019; 137: 9–17.

[4] Chargari C, Peignaux K, Escande A, Renard S, Lafond C, Petit A, et al. Radiotherapy of cervical cancer. Cancer Radiotherapie. 2022; 26: 298–308.

[5] Musunuru HB, Pifer PM, Mohindra P, Albuquerque K, Beriwal S. Advances in management of locally advanced cervical cancer. Indian Journal of Medical Research. 2021; 154: 248–261.

[6] Ouellette MM, Zhou S, Yan Y. Cell signaling pathways that promote radioresistance of cancer cells. Diagnostics. 2022; 12: 656.

[7] Yin J, Zhu JM, Shen XZ. New insights into pre-mRNA processing factor 19: a multi-faceted protein in humans. Biology of the Cell. 2012; 104: 695–705.

[8] Chanarat S, Sträßer K. Splicing and beyond: the many faces of the Prp19 complex. Biochimica et Biophysica Acta. 2013; 1833: 2126–2134.

[9] He Y, Huang C, Cai K, Liu P, Chen X, Xu YI, et al. PRPF19 promotes tongue cancer growth and chemoradiotherapy resistance. Acta Biochimica et Biophysica Sinica. 2021; 53: 893–902.

[10] Zhang G, Zhang W, Dan M, Zou F, Qiu C, Sun C. PRPF19 promotes the proliferation, migration, and inhibits autophagy in prostate cancer by suppressing SLC40A1. Chinese Journal of Physiology. 2023; 66: 379–387.

[11] Yu J, Ge S. PRPF19 functions in DNA damage repair and gemcitabine sensitivity via regulating DDB1 in bladder cancer cells. Cytotechnology. 2024; 76: 85–96.

[12] Zhang GC, Yu XN, Guo HY, Sun JL, Liu ZY, Zhu JM, et al. PRP19 enhances esophageal squamous cell carcinoma progression by reprogramming SREBF1-dependent fatty acid metabolism. Cancer Research. 2023; 83: 521–537.

[13] Zhou R, Chen J, Xu Y, Ye Y, Zhong G, Chen T, et al. PRPF19 facilitates colorectal cancer liver metastasis through activation of the Src-YAP1 pathway via K63-linked ubiquitination of MYL9. Cell Death & Disease. 2023; 14: 258.

[14] Song Q, Wen J, Li W, Xue J, Zhang Y, Liu H, et al. HSP90 promotes radioresistance of cervical cancer cells via reducing FBXO6-mediated CD147 polyubiquitination. Cancer Science. 2022; 113: 1463–1474.

[15] Huang Y, Tian Y, Zhang W, Liu R, Zhang W. Rab12 promotes radioresistance of HPV-positive cervical cancer cells by increasing G2/M arrest. Frontiers in Oncology. 2021; 11: 586771.

[16] Deng YR, Chen XJ, Chen W, Wu LF, Jiang HP, Lin D, et al. Sp1 contributes to radioresistance of cervical cancer through targeting G2/M cell cycle checkpoint CDK1. Cancer Management and Research. 2019; 11: 5835–5844.

[17] Huang RX, Zhou PK. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduction and Targeted Therapy. 2020; 5: 60.

[18] Suwa T, Kobayashi M, Nam JM, Harada H. Tumor microenvironment and radioresistance. Experimental & Molecular Medicine. 2021; 53: 1029–1035.

[19] Gillespie MS, Ward CM, Davies CC. DNA repair and therapeutic strategies in cancer stem cells. Cancers. 2023; 15: 1897.

[20] Zhou J, Lei N, Qin B, Chen M, Gong S, Sun H, et al. Aldolase A promotes cervical cancer cell radioresistance by regulating the glycolysis and DNA damage after irradiation. Cancer Biology & Therapy. 2023; 24: 2287128.

[21] Ni M, Li J, Zhao H, Xu F, Cheng J, Yu M, et al. BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair. Oncogene. 2021; 40: 2711–2724.

[22] Wei X, Sun K, Li S, Lin C, Wei Z. PSME3 induces radioresistance and enhances aerobic glycolysis in cervical cancer by regulating PARP1. Tissue and Cell. 2023; 83: 102151.

[23] Fu X, Duan Z, Lu X, Zhu Y, Ren Y, Zhang W, et al. SND1 promotes radioresistance in cervical cancer cells by targeting the DNA damage response. Cancer Biotherapy and Radiopharmaceuticals. 2024; 39: 425–434.

[24] Yu C, Zhang M, Song J, Zheng X, Xu G, Bao Y, et al. Integrin-Src-YAP1 signaling mediates the melanoma acquired resistance to MAPK and PI3K/mTOR dual targeted therapy. Molecular Biomedicine. 2020; 1: 12.

[25] Li P, Silvis MR, Honaker Y, Lien WH, Arron ST, Vasioukhin V. αE-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway. Genes & Development. 2016; 30: 798–811.

[26] Duan Y, Kong P, Huang M, Yan Y, Dou Y, Huang B, et al. STAT3-mediated up-regulation of DAB2 via SRC-YAP1 signaling axis promotes Helicobacter pylori-driven gastric tumorigenesis. Biomarker Research. 2024; 12: 33.