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FGD3 binds with HSF4 to suppress p65 expression and inhibit pancreatic cancer progression

Oncogene volume 41, pages 838–851 (2022)Cite this article

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Abstract

Pancreatic cancer is regarded as the most lethal solid tumor worldwide. Deregulated and constitutively activated NF-κB signaling is one of the major characteristics of pancreatic cancer. The total expression level and subcellular localization of RelA/p65 have been shown to determine the activation of canonical NF-κB signaling in pancreatic cancer. FGD3, which is involved in regulating the actin cytoskeleton and cell shape, has been reported to inhibit cancer cell migration and predict a favorable prognosis in multiple types of cancer. However, the specific role of FGD3 in pancreatic cancer is still unknown. In this study, we conducted a systematic investigation of the cancer-related role of FGD3 in pancreatic cancer. We demonstrated that FGD3 was abnormally downregulated in pancreatic cancer tissues and that low expression of FGD3 was associated with unfavorable prognosis in patients with pancreatic cancer. Then, we showed that FGD3 inhibited pancreatic cancer cell proliferation, invasion and metastasis in vivo and in vitro. Moreover, we revealed that FGD3 silencing activated the NF-κB signaling pathway by promoting HSF4 nuclear translocation and increasing p65 expression in pancreatic cancer cells. Therefore, our results identified a novel and targetable FGD3/HSF4/p65 signaling axis in pancreatic cancer cells.

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Fig. 1: FGD3 is downregulated and is a predictor of favorable prognosis in pancreatic cancer.
Fig. 2: FGD3 inhibits pancreatic cancer progression in vitro.
Fig. 3: The cancer-promoting effect of knocking down FGD3 can be rescued by overexpression of FGD3.
Fig. 4: FGD3 inactivates NF-κB signaling in pancreatic cancer.
Fig. 5: FGD3 suppresses p65 expression to modulate pancreatic cancer cell progression.
Fig. 6: FGD3 interacted with HSF4 to prevent nuclear entry of HSF4.
Fig. 7: The FGD3/HSF4 axis regulates p65 expression in pancreatic cancer.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding authors (Xin Jin, jinxinxy2@csu.edu.cn) on reasonable request.

References

  1. Khalaf N, El-Serag HB, Abrams HR, Thrift AP. Burden of pancreatic cancer: from epidemiology to practice. Clin Gastroenterol Hepatol. 2021;19:876–84.

    Article  PubMed  Google Scholar 

  2. Kabacaoglu D, Ruess DA, Ai J, Algul H. NF-kappaB/rel transcription factors in pancreatic cancer: focusing on RelA, c-Rel, and RelB. Cancers (Basel) 2019;11:937.

  3. Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125:3335–7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cable J, Greenbaum B, Pe’er D, Bollard CM, Bruni S, Griffin ME, et al. Frontiers in cancer immunotherapy-a symposium report. Ann N. Y Acad Sci. 2021;1489:30–47.

    Article  CAS  PubMed  Google Scholar 

  5. Wu J, Cai J. Dilemma and challenge of immunotherapy for pancreatic cancer. Dig Dis Sci. 2021;66:359–68.

    Article  PubMed  Google Scholar 

  6. Dougan SK. The pancreatic cancer microenvironment. Cancer J. 2017;23:321–5.

    Article  PubMed  Google Scholar 

  7. Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67:9518–27.

    Article  CAS  PubMed  Google Scholar 

  8. Hanson JL, Hawke NA, Kashatus D, Baldwin AS. The nuclear factor kappaB subunits RelA/p65 and c-Rel potentiate but are not required for Ras-induced cellular transformation. Cancer Res. 2004;64:7248–55.

    Article  CAS  PubMed  Google Scholar 

  9. Finco TS, Westwick JK, Norris JL, Beg AA, Der CJ, Baldwin AS Jr. Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J Biol Chem. 1997;272:24113–6.

    Article  CAS  PubMed  Google Scholar 

  10. Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:105–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Makieva S, Dubicke A, Rinaldi SF, Fransson E, Ekman-Ordeberg G, Norman JE. The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes. Am J Obstet Gynecol. 2017;216:602 e601–602 e621.

    Article  CAS  Google Scholar 

  12. Nakanishi H, Takai Y. Frabin and other related Cdc42-specific guanine nucleotide exchange factors couple the actin cytoskeleton with the plasma membrane. J Cell Mol Med. 2008;12:1169–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Willis S, Sun Y, Abramovitz M, Fei T, Young B, Lin X, et al. High expression of FGD3, a putative regulator of cell morphology and motility, is prognostic of favorable outcome in multiple cancers. JCO Precis Oncol. 2017;1: PO.17.00009.

  14. Susini T, Renda I. FGD3 gene as a new prognostic factor in breast cancer. Anticancer Res. 2020;40:3645–9.

    Article  CAS  PubMed  Google Scholar 

  15. Renda I, Bianchi S, Vezzosi V, Nori J, Vanzi E, Tavella K, et al. Expression of FGD3 gene as prognostic factor in young breast cancer patients. Sci Rep. 2019;9:15204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ma C, Li H, Li X, Lu S, He J. The prognostic value of faciogenital dysplasias as biomarkers in head and neck squamous cell carcinoma. Biomark Med. 2019;13:1399–415.

    Article  CAS  PubMed  Google Scholar 

  17. Jing B, Qian R, Jiang D, Gai Y, Liu Z, Guo F, et al. Extracellular vesicles-based pre-targeting strategy enables multi-modal imaging of orthotopic colon cancer and image-guided surgery. J Nanobiotechnology. 2021;19:151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jing B, Gai Y, Qian R, Liu Z, Zhu Z, Gao Y, et al. Hydrophobic insertion-based engineering of tumor cell-derived exosomes for SPECT/NIRF imaging of colon cancer. J Nanobiotechnology. 2021;19:7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walter W, Sanchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics. 2015;31:2912–4.

    Article  CAS  PubMed  Google Scholar 

  21. Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, et al. Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell. 2013;154:801–13.

    Article  CAS  PubMed  Google Scholar 

  22. Fan P, Zhao J, Meng Z, Wu H, Wang B, Wu H, et al. Overexpressed histone acetyltransferase 1 regulates cancer immunity by increasing programmed death-ligand 1 expression in pancreatic cancer. J Exp Clin Cancer Res. 2019;38:47.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chen R, Liliental JE, Kowalski PE, Lu Q, Cohen SN. Regulation of transcription of hypoxia-inducible factor-1alpha (HIF-1alpha) by heat shock factors HSF2 and HSF4. Oncogene. 2011;30:2570–80.

    Article  CAS  PubMed  Google Scholar 

  24. Neumann M, Naumann M. Beyond IkappaBs: alternative regulation of NF-kappaB activity. FASEB J. 2007;21:2642–54.

    Article  CAS  PubMed  Google Scholar 

  25. Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004;6:203–8.

    Article  CAS  PubMed  Google Scholar 

  26. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999;5:119–27.

    CAS  PubMed  Google Scholar 

  27. Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18:6938–47.

    Article  CAS  PubMed  Google Scholar 

  28. Kong R, Sun B, Jiang H, Pan S, Chen H, Wang S, et al. Downregulation of nuclear factor-kappaB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer. Cancer Lett. 2010;291:90–8.

    Article  CAS  PubMed  Google Scholar 

  29. Pan X, Arumugam T, Yamamoto T, Levin PA, Ramachandran V, Ji B, et al. Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res. 2008;14:8143–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Matsuo Y, Sawai H, Funahashi H, Takahashi H, Sakamoto M, Yamamoto M, et al. Enhanced angiogenesis due to inflammatory cytokines from pancreatic cancer cell lines and relation to metastatic potential. Pancreas. 2004;28:344–52.

    Article  CAS  PubMed  Google Scholar 

  31. Wang L, Wu H, Wang L, Zhang H, Lu J, Liang Z, et al. Asporin promotes pancreatic cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition (EMT) through both autocrine and paracrine mechanisms. Cancer Lett. 2017;398:24–36.

    Article  CAS  PubMed  Google Scholar 

  32. Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, et al. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation. Mol Cancer. 2016;15:3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Meng Q, Liang C, Hua J, Zhang B, Liu J, Zhang Y, et al. A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: functional validation and clinical significance. Theranostics. 2020;10:3967–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang L, Zhou W, Zhong Y, Huo Y, Fan P, Zhan S, et al. Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-kappaB signaling pathway. Mol Cancer. 2017;16:61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jin X, Ding D, Yan Y, Li H, Wang B, Ma L, et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-kappaB activation and PD-L1 expression. Mol Cell. 2019;73:22–35 e26.

    Article  CAS  PubMed  Google Scholar 

  36. Abane R, Mezger V. Roles of heat shock factors in gametogenesis and development. FEBS J. 2010;277:4150–72.

    Article  CAS  PubMed  Google Scholar 

  37. Fujimoto M, Izu H, Seki K, Fukuda K, Nishida T, Yamada S, et al. HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 2004;23:4297–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shi X, Cui B, Wang Z, Weng L, Xu Z, Ma J, et al. Removal of Hsf4 leads to cataract development in mice through down-regulation of gamma S-crystallin and Bfsp expression. BMC Mol Biol. 2009;10:10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Liao S, Qu Z, Li L, Zhou B, Gao M, Huang M, et al. HSF4 transcriptional regulates HMOX-1 expression in HLECs. Gene. 2018;655:30–4.

    Article  CAS  PubMed  Google Scholar 

  40. Cui X, Zhang J, Du R, Wang L, Archacki S, Zhang Y, et al. HSF4 is involved in DNA damage repair through regulation of Rad51. Biochim Biophys Acta. 2012;1822:1308–15.

    Article  CAS  PubMed  Google Scholar 

  41. Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat shock proteins and cancer. Trends Pharm Sci. 2017;38:226–56.

    Article  CAS  PubMed  Google Scholar 

  42. Yang Y, Jin L, Zhang J, Wang J, Zhao X, Wu G, et al. High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer. IUBMB Life. 2017;69:956–61.

    Article  CAS  PubMed  Google Scholar 

  43. Jin X, Eroglu B, Cho W, Yamaguchi Y, Moskophidis D, Mivechi NF. Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo. Mol Cancer Res. 2012;10:523–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ma P, Tang WG, Hu JW, Hao Y, Xiong LK, Wang MM, et al. HSP4 triggers epithelial-mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT. Liver Int. 2020;40:1211–23.

    Article  CAS  PubMed  Google Scholar 

  45. Pasteris NG, Nagata K, Hall A, Gorski JL. Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue. Gene. 2000;242:237–47.

    Article  CAS  PubMed  Google Scholar 

  46. Oshima T, Fujino T, Ando K, Hayakawa M. Proline-rich domain plays a crucial role in extracellular stimuli-responsive translocation of a Cdc42 guanine nucleotide exchange factor, FGD1. Biol Pharm Bull. 2010;33:35–9.

    Article  CAS  PubMed  Google Scholar 

  47. Wu W, Jing D, Meng Z, Hu B, Zhong B, Deng X, et al. FGD1 promotes tumor progression and regulates tumor immune response in osteosarcoma via inhibiting PTEN activity. Theranostics. 2020;10:2859–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82073178 (H.W.), Grant No. 82073321 (X.J.)) and Science Foundation of Ministry of Education of China (Grant No. 2172019kfyRCPY069 (X.J.)).

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Authors and Affiliations

  1. Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Feng Guo & Heshui Wu

  2. Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Feng Guo & Heshui Wu

  3. Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Xiang Cheng

  4. Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P.R. China

    Boping Jing

  5. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China

    Xin Jin

  6. Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China

    Xin Jin

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  1. Feng Guo
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Contributions

XJ: funding acquisition, investigation, methodology, project administration, writing - original draft. HW: funding acquisition, project administration, writing - original draft. BJ: PET-CT imaging and analysis. XC: conceptualization, supervision, project administration. FG: software, formal analysis, methodology.

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Correspondence to Heshui Wu or Xin Jin.

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Guo, F., Cheng, X., Jing, B. et al. FGD3 binds with HSF4 to suppress p65 expression and inhibit pancreatic cancer progression. Oncogene 41, 838–851 (2022). https://doi.org/10.1038/s41388-021-02140-6

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