Research Progress on the Relationship Between WSTF and Cancere

Yunjie Pei; Yan Liu; Shuqing Wang; Yuanyue Zhang; Jinghua Zhang

doi:10.71204/mny7mr80

Authors

Yunjie Pei Affiliated Hospital of North China University of Science and Technology Author
Yan Liu North China University of Science and Technology Author
Shuqing Wang Hospital of North China University of Science and Technology Author
Yuanyue Zhang Center Laboratory of Nanjing Medical University BenQ hospital Suzhou Campus Author
Jinghua Zhang Department of Tangshan Maternal and Child Health Hospital Author

DOI:

https://doi.org/10.71204/mny7mr80

Keywords:

WSTF, Malignant Tumors, Transcriptional Regulation, PI3K/Akt Pathway

Abstract

The Williams syndrome transcription factor (WSTF, alternatively termed BAZ1B) represents a versatile nuclear protein that exerts pleiotropic effects on neurodevelopmental processes, chromatin remodeling, DNA damage repair, as well as transcriptional regulation. Accumulating evidence demonstrates that WSTF is a crucial molecular determinant in the pathogenesis and progression of multiple cancers, positioning it as a viable therapeutic target. This review systematically synthesizes the molecular mechanisms by which WSTF drives oncogenesis across malignancies, focusing on its interplay with regulatory factors and signaling pathways. In breast cancer, WSTF participates in estrogen receptor (ER) signaling and contributes to endocrine therapy resistance by modulating ER-dependent gene expression to promote proliferation and invasion. WSTF also interacts with the vitamin D analog EB1089, suppressing tumor progression through altered promoter binding. In gastric cancer, aberrant WSTF expression disrupts cell adhesion, increasing cancer cell dependency on WSTF. Hyperphosphorylation of WSTF in diffuse gastric cancer further implicates it in tumorigenesis. In cervical, glioblastoma, and lung cancers, WSTF activates the PI3K-Akt signaling cascade, enhancing tumor cell proliferation, migration, and invasion. These findings underscore WSTF’s oncogenic role and therapeutic potential. Further investigation into WSTF’s functions and regulatory mechanisms will deepen our understanding of tumorigenesis and inform novel therapies targeting this chromatin regulator.

References

Allegri, L., Baldan, F., Mio, C., De Felice, M., Amendola, E., & Damante, G. (2020). BAZ1B is a candidate gene responsible for hypothyroidism in Williams syndrome. Eur J Med Genet, 63(6), 103894.

Aydin Ö, Z., Marteijn, J. A., Ribeiro-Silva, C., Rodríguez López, A., Wijgers, N., Smeenk, G., van Attikum, H., Poot, R. A., Vermeulen, W., & Lans, H. (2014). Human ISWI complexes are targeted by SMARCA5 ATPase and SLIDE domains to help resolve lesion-stalled transcription. Nucleic Acids Res, 42(13), 8473-8485.

Bajbouj, K., Al-Ali, A., Shafarin, J., Sahnoon, L., Sawan, A., Shehada, A., Elkhalifa, W., Saber-Ayad, M., Muhammad, J. S., Elmoselhi, A. B., Guraya, S. Y., & Hamad, M. (2022). Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells. Front Oncol, 12, 918340.

Barnett, C., & Krebs, J. E. (2011). WSTF does it all: a multifunctional protein in transcription, repair, and replication. Biochem Cell Biol, 89(1), 12-23.

Barnett, C., & Krebs, J. E. (2011). WSTF does it all: a multifunctional protein in transcription, repair, and replicationThis paper is one of a selection of papers published in a Special Issue entitled 31st Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process. Biochemistry and Cell Biology, 89(1), 12-23.

Bellugi, U., Bihrle, A., Jernigan, T., Trauner, D., & Doherty, S. (1990). Neuropsychological, neurological, and neuroanatomical profile of Williams syndrome. Am J Med Genet Suppl, 6, 115-125.

Broering, T. J., Wang, Y. L., Pandey, R. N., Hegde, R. S., Wang, S. C., & Namekawa, S. H. (2015). BAZ1B is dispensable for H2AX phosphorylation on Tyrosine 142 during spermatogenesis. Biol Open, 4(7), 873-884.

Bulun, S. E., Lin, Z., Zhao, H., Lu, M., Amin, S., Reierstad, S., & Chen, D. (2009). Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci, 1155, 121-131.

Dennis, C., Dillon, J., Cohen, D. J., Halquist, M. S., Pearcy, A. C., Schwartz, Z., & Boyan, B. D. (2023). Local production of active vitamin D(3) metabolites in breast cancer cells by CYP24A1 and CYP27B1. J Steroid Biochem Mol Biol, 232, 106331.

Dibitetto, D., Liptay, M., Vivalda, F., Dogan, H., Gogola, E., González Fernández, M., Duarte, A., Schmid, J. A., Decollogny, M., Francica, P., Przetocka, S., Durant, S. T., Forment, J. V., Klebic, I., Siffert, M., de Bruijn, R., Kousholt, A. N., Marti, N. A., Dettwiler, M., . . . Rottenberg, S. (2024). H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours. Nat Commun, 15(1), 4430.

Geiger, R., Rieckmann, J. C., Wolf, T., Basso, C., Feng, Y., Fuhrer, T., Kogadeeva, M., Picotti, P., Meissner, F., Mann, M., Zamboni, N., Sallusto, F., & Lanzavecchia, A. (2016). L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell, 167(3), 829-842.

Goto, N., Suke, K., Yonezawa, N., Nishihara, H., Handa, T., Sato, Y., Kujirai, T., Kurumizaka, H., Yamagata, K., & Kimura, H. (2024). ISWI chromatin remodeling complexes recruit NSD2 and H3K36me2 in pericentromeric heterochromatin. J Cell Biol, 223(8), e202310084.

Grochowska, A., Statkiewicz, M., Kulecka, M., Cybulska, M., Sandowska-Markiewicz, Z., Kopczynski, M., Drezinska-Wolek, E., Tysarowski, A., Prochorec-Sobieszek, M., Ostrowski, J., & Mikula, M. (2022). Evidence supporting the oncogenic role of BAZ1B in colorectal cancer. Am J Cancer Res, 12(10), 4751-4763.

Hill, N. T., Zhang, J., Leonard, M. K., Lee, M., Shamma, H. N., & Kadakia, M. (2015). 1α, 25-Dihydroxyvitamin D₃ and the vitamin D receptor regulates ΔNp63α levels and keratinocyte proliferation. Cell Death Dis, 6(6), e1781.

Ji, J. H., Min, S., Chae, S., Ha, G. H., Kim, Y., Park, Y. J., Lee, C. W., & Cho, H. (2019). De novo phosphorylation of H2AX by WSTF regulates transcription-coupled homologous recombination repair. Nucleic Acids Res, 47(12), 6299-6314.

Jiang, D., Ren, C., Yang, L., Li, F., Yang, X., Zheng, Y., Ji, X., & Tian, Y. (2021). Williams syndrome transcription factor promotes proliferation and invasion of cervical cancer cells by regulating PI3K/Akt signaling pathway. J Obstet Gynaecol Res, 47(7), 2433-2441.

Kamaraju, S., Drope, J., Sankaranarayanan, R., & Shastri, S. (2020). Cancer Prevention in Low-Resource Countries: An Overview of the Opportunity. American Society of Clinical Oncology Educational Book, (40), 72-83.

Kim, K. K., Kugler, M. C., Wolters, P. J., Robillard, L., Galvez, M. G., Brumwell, A. N., Sheppard, D., & Chapman, H. A. (2006). Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A, 103(35), 13180-13185.

Lalli, M. A., Jang, J., Park, J. H., Wang, Y., Guzman, E., Zhou, H., Audouard, M., Bridges, D., Tovar, K. R., Papuc, S. M., Tutulan-Cunita, A. C., Huang, Y., Budisteanu, M., Arghir, A., & Kosik, K. S. (2016). Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways. Hum Mol Genet, 25(7), 1294-1306.

Li, C., Y, Liu, Y., Deng, Y., Wang, S., Q, Song, M., Z, Chen, S., Chang, J., F, & Yang, Z., Y. (2016). H3K9ac and H4K16ac were Regulated Through PCAF/WSTF/MOF Com

plex in Breast Cancer Cells. Genomics and Applied Biology, 35(05), 1008-1012.

Li, Y., Gong, H., Wang, P., Zhu, Y., Peng, H., Cui, Y., Li, H., Liu, J., & Wang, Z. (2021). The emerging role of ISWI chromatin remodeling complexes in cancer. J Exp Clin Cancer Res, 40(1), 346.

Lin, C. H., Zahid, M., Kuo, W. H., Hu, F. C., Wang, M. Y., Chen, I. C., Beseler, C. L., Mondal, B., Lu, Y. S., Rogan, E. G., & Cheng, A. L. (2023). Estrogen-DNA Adducts and Breast Cancer Risk in Premenopausal Asian Women. Cancer Prev Res (Phila), 16(3), 153-161.

Liu, Y., Wang, S. Q., Long, Y. H., Chen, S., Li, Y. F., & Zhang, J. H. (2016). KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway. Oncotarget, 7(33), 53153-53164.

Liu, Y., Zhang, Y.-Y., Wang, S.-Q., Li, M., Long, Y.-H., Li, Y.-F., Liu, Y.-K., Li, Y.-H., Wang, Y.-Q., Mi, J.-S., Yu, C.-H., Li, D.-Y., Zhang, J.-H., & Zhang, X.-J. (2020). WSTF acetylation by MOF promotes WSTF activities and oncogenic functions. Oncogene, 39(27), 5056-5067.

Luengo-Fernandez, R., Leal, J., Gray, A., & Sullivan, R. (2013). Economic burden of cancer across the European Union: a population-based cost analysis. Lancet Oncol, 14(12), 1165-1174.

Lundqvist, J., Hansen, S. K., & Lykkesfeldt, A. E. (2013). Vitamin D analog EB1089 inhibits aromatase expression by dissociation of comodulator WSTF from the CYP19A1 promoter—a new regulatory pathway for aromatase. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1833(1), 40-47.

Lundqvist, J., Kirkegaard, T., Laenkholm, A. V., Duun-Henriksen, A. K., Bak, M., Feldman, D., & Lykkesfeldt, A. E. (2018). Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1α,25-dihydroxyvitamin D(3). J Steroid Biochem Mol Biol, 177, 171-178.

Maga, G., & Hubscher, U. (2003). Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci, 116(Pt 15), 3051-3060.

Meng, J., Zhang, X. T., Liu, X. L., Fan, L., Li, C., Sun, Y., Liang, X. H., Wang, J. B., Mei, Q. B., Zhang, F., & Zhang, T. (2016). WSTF promotes proliferation and invasion of lung cancer cells by inducing EMT via PI3K/Akt and IL-6/STAT3 signaling pathways. Cell Signal, 28(11), 1673-1682.

Mittal, V. (2016). Epithelial Mesenchymal Transition in Aggressive Lung Cancers. Adv Exp Med Biol, 890, 37-56.

Nargund, A. M., Xu, C., Mandoli, A., Okabe, A., Chen, G. B., Huang, K. K., Sheng, T., Yao, X., Teo, J. M. N., Sundar, R., Kok, Y. J., See, Y. X., Xing, M., Li, Z., Yong, C. H., Anand, A., A, I. Z., Poon, L. F., Ng, M. S. W., . . . Tan, P. (2022). Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer. Cancer Res, 82(14), 2538-2551.

Nargund, A. M., Xu, C., Mandoli, A., Okabe, A., Chen, G. B., Huang, K. K., Sheng, T., Yao, X., Teo, J. M. N., Sundar, R., Kok, Y. J., See, Y. X., Xing, M., Li, Z., Yong, C. H., Anand, A., Bin Adam Isa, Z. F., Poon, L. F., Ng, M. S. W., . . . Tan, P. (2023). Correction: Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer. Cancer Res, 83(5), 804.

Nelson, L. R., & Bulun, S. E. (2001). Estrogen production and action. J Am Acad Dermatol, 45(3 Suppl), S116-124.

Oppikofer, M., Sagolla, M., Haley, B., Zhang, H. M., Kummerfeld, S. K., Sudhamsu, J., Flynn, E. M., Bai, T., Zhang, J., Ciferri, C., & Cochran, A. G. (2017). Non-canonical reader modules of BAZ1A promote recovery from DNA damage. Nat Commun, 8(1), 862.

Percipalle, P., Fomproix, N., Cavellán, E., Voit, R., Reimer, G., Krüger, T., Thyberg, J., Scheer, U., Grummt, I., & Farrants, A. K. (2006). The chromatin remodelling complex WSTF-SNF2h interacts with nuclear myosin 1 and has a role in RNA polymerase I transcription. EMBO Rep, 7(5), 525-530.

Poot, R. A., Bozhenok, L., van den Berg, D. L., Hawkes, N., & Varga-Weisz, P. D. (2005). Chromatin remodeling by WSTF-ISWI at the replication site: opening a window of opportunity for epigenetic inheritance? Cell Cycle, 4(4), 543-546.

Poot, R. A., Bozhenok, L., van den Berg, D. L., Steffensen, S., Ferreira, F., Grimaldi, M., Gilbert, N., Ferreira, J., & Varga-Weisz, P. D. (2004). The Williams syndrome transcription factor interacts with PCNA to target chromatin remodelling by ISWI to replication foci. Nat Cell Biol, 6(12), 1236-1244.

Powell, K., Haslam, A., & Prasad, V. (2022). An Empirical Analysis of Precision Previvorship: Are Familial and High-Risk Cancer Preventive Programs Evidence Based? Am J Med, 135(2), 179-183.

Qiu, X., Zhang, K., Zhang, Y., & Sun, L. (2022). Benefit Finding and Related Factors of Patients with Early-Stage Cancer in China. International Journal of Environmental Research and Public Health, 19(7), 4284.

Saatci, O., Huynh-Dam, K. T., & Sahin, O. (2021). Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. J Mol Med (Berl), 99(12), 1691-1710.

Salvati, A., Melone, V., Sellitto, A., Rizzo, F., Tarallo, R., Nyman, T. A., Giurato, G., Nassa, G., & Weisz, A. (2022). Combinatorial targeting of a chromatin complex comprising Dot1L, menin and the tyrosine kinase BAZ1B reveals a new therapeutic vulnerability of endocrine therapy-resistant breast cancer. Breast Cancer Res, 24(1), 52.

Sammons, S., Sedrak, M. S., & Kimmick, G. G. (2020). The Evolving Complexity of Treating Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2 (HER2)-Negative Breast Cancer: Special Considerations in Older Breast Cancer Patients-Part I: Early-Stage Disease. Drugs Aging, 37(5), 331-348.

Sarshad, A., Sadeghifar, F., Louvet, E., Mori, R., Böhm, S., Al-Muzzaini, B., Vintermist, A., Fomproix, N., Östlund, A. K., & Percipalle, P. (2013). Nuclear myosin 1c facilitates the chromatin modifications required to activate rRNA gene transcription and cell cycle progression. PLoS Genet, 9(3), e1003397.

Schnell, U., Cirulli, V., & Giepmans, B. N. (2013). EpCAM: structure and function in health and disease. Biochim Biophys Acta, 1828(8), 1989-2001.

Serrano-Juárez, C. A., Prieto-Corona, B., Rodríguez-Camacho, M., Sandoval-Lira, L., Villalva-Sánchez Á, F., Yáñez-Téllez, M. G., & López, M. F. R. (2023). Neuropsychological Genotype-Phenotype in Patients with Williams Syndrome with Atypical Deletions: A Systematic Review. Neuropsychol Rev, 33(4), 891-911.

Sharif, S. B., Zamani, N., & Chadwick, B. P. (2021). BAZ1B the Protean Protein. Genes (Basel), 12(10), 1541.

Simpson, E. R. (2004). Aromatase: biologic relevance of tissue-specific expression. Semin Reprod Med, 22(1), 11-23.

Singh, S., Parthasarathi, K. T. S., Bhat, M. Y., Gopal, C., Sharma, J., & Pandey, A. (2024). Profiling Kinase Activities for Precision Oncology in Diffuse Gastric Cancer. OMICS: A Journal of Integrative Biology, 28(2), 76-89.

Stemmer, S. M., Mahal, A., Karan, A., Fan, V. Y., & Engelgau, M. (2013). The Economic Burden of Cancers on Indian Households. PLoS One, 8(8), e71853.

Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3), 209-249.

Tsukita, S., Tanaka, H., & Tamura, A. (2019). The Claudins: From Tight Junctions to Biological Systems. Trends Biochem Sci, 44(2), 141-152.

Venit, T., Mahmood, S. R., Endara-Coll, M., & Percipalle, P. (2020). Nuclear actin and myosin in chromatin regulation and maintenance of genome integrity. Int Rev Cell Mol Biol, 355, 67-108.

Vintermist, A., Böhm, S., Sadeghifar, F., Louvet, E., Mansén, A., Percipalle, P., & Ostlund Farrants, A. K. (2011). The chromatin remodelling complex B-WICH changes the chromatin structure and recruits histone acetyl-transferases to active rRNA genes. PLoS One, 6(4), e19184.

Will, M., Liang, J., Metcalfe, C., & Chandarlapaty, S. (2023). Therapeutic resistance to anti-oestrogen therapy in breast cancer. Nat Rev Cancer, 23(10), 673-685.

Xiao, A., Li, H., Shechter, D., Ahn, S. H., Fabrizio, L. A., Erdjument-Bromage, H., Ishibe-Murakami, S., Wang, B., Tempst, P., Hofmann, K., Patel, D. J., Elledge, S. J., & Allis, C. D. (2009). WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature, 457(7225), 57-62.

Yabroff, K. R., Lund, J., Kepka, D., & Mariotto, A. (2011). Economic burden of cancer in the United States: estimates, projections, and future research. Cancer Epidemiol Biomarkers Prev, 20(10), 2006-2014.

Yang, L., Du, C., Chen, H., & Diao, Z. (2021). Downregulation of Williams syndrome transcription factor (WSTF) suppresses glioblastoma cell growth and invasion by inhibiting PI3K/AKT signal pathway. Eur J Histochem, 65(4), 3255.

Yang, S., Quaresma, A. J., Nickerson, J. A., Green, K. M., Shaffer, S. A., Imbalzano, A. N., Martin-Buley, L. A., Lian, J. B., Stein, J. L., van Wijnen, A. J., & Stein, G. S. (2015). Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response. J Cell Sci, 128(4), 728-740.

Yuan, J., Adamski, R., & Chen, J. (2010). Focus on histone variant H2AX: to be or not to be. FEBS Lett, 584(17), 3717-3724.

Zanella, M., Vitriolo, A., Andirko, A., Martins, P. T., Sturm, S., O'Rourke, T., Laugsch, M., Malerba, N., Skaros, A., Trattaro, S., Germain, P. L., Mihailovic, M., Merla, G., Rada-Iglesias, A., Boeckx, C., & Testa, G. (2019). Dosage analysis of the 7q11.23 Williams region identifies BAZ1B as a major human gene patterning the modern human face and underlying self-domestication. Sci Adv, 5(12), eaaw7908.

Zeisberg, E. M., Tarnavski, O., Zeisberg, M., Dorfman, A. L., McMullen, J. R., Gustafsson, E., Chandraker, A., Yuan, X., Pu, W. T., Roberts, A. B., Neilson, E. G., Sayegh, M. H., Izumo, S., & Kalluri, R. (2007). Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med, 13(8), 952-961.

Zhou, J., Zheng, Y., Liang, G., Xu, X., Liu, J., Chen, S., Ge, T., Wen, P., Zhang, Y., Liu, X., Zhuang, J., Wu, Y., & Chen, J. (2022). Atypical deletion of Williams-Beuren syndrome reveals the mechanism of neurodevelopmental disorders. BMC Med Genomics, 15(1), 79.