DPY30 promotes the growth and survival of osteosarcoma cell by regulating the PI3K/AKT signal pathway

Submitted: 27 March 2022
Accepted: 11 September 2022
Published: 22 December 2022
Abstract Views: 680
PDF: 406
Supplementary: 48
HTML: 14
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Osteosarcoma (OS) is characterized by aggressive features including invasiveness and high incidence of metastasis. OS patients with metastases are difficult to treat and suffer from a poor prognosis. DPY30 (protein dpy-30 homolog) is a key component of SET1/MLL family of H3K4 methyltransferases, which is implicated in the progression of multiple cancers. However, the potential functional engagement of DPY30 in OS remains to be unveiled. The objective of this study is to investigate the potential roles of DPY30 in the regulation of malignant phenotypes of OS cells. We examined DPY30 expression from a published dataset (GSE28424) as well as in OS tissues and adjacent normal tissues from OS patients. The association of DPY30 expression level and clinicopathologic parameters was assessed by Chi-square test. The role of DPY30 in regulating the malignant phenotype of OS cells and tumorigenesis was examined by in vitro functional assays and xenograft mouse model. We reported an upregulation of DPY30 in OS tumor tissues in both published dataset and clinical samples. A high level of DPY30 expression was associated with larger tumor size and more metastasis in OS patients, as well as poor overall survival. DPY30 knockdown in OS cells significantly impairs proliferation, migration and invasion, but induced cellular apoptosis. We further demonstrated that the agonist of PI3K/AKT pathway can rescue the inhibitory effects of DPY30 knockdown in OS cells. Together, our data indicate that DPY30 functions as an oncogene to promote the malignancy of OS cells possibly through PI3K/AKT pathway. The dependency of OS cells on DPY30 overexpression is a targetable vulnerability in OS cells.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Kansara M, Teng MW, Smyth MJ, Thomas DM. Translational biology of osteosarcoma. Nat Rev Cancer 2014;14:722-35. DOI: https://doi.org/10.1038/nrc3838
Gill J, Gorlick R. Advancing therapy for osteosarcoma. Nat Rev Clin Oncol 2021;18:609-24. DOI: https://doi.org/10.1038/s41571-021-00519-8
Smeland S, Bielack SS, Whelan J, Bernstein M, Hogendoorn P, Krailo MD, et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer 2019;109:36-50. DOI: https://doi.org/10.1016/j.ejca.2018.11.027
Kane GM, Cadoo KA, Walsh EM, Emerson R, Dervan P, O’Keane C, et al. Perioperative chemotherapy in the treatment of osteosarcoma: a 26-year single institution review. Clin Sarcoma Res 2015;5:17. DOI: https://doi.org/10.1186/s13569-015-0032-0
Kim W, Han I, Lee JS, Cho HS, Park JW, Kim H-S. Postmetastasis survival in high-grade extremity osteosarcoma: A retrospective analysis of prognostic factors in 126 patients. J Surg Oncol 2018;117:1223-31. DOI: https://doi.org/10.1002/jso.24963
McGuire JJ, Nerlakanti N, Lo CH, Tauro M, Utset-Ward TJ, Reed DR, et al. Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma. Int J Cancer 2020;147:2811-23. DOI: https://doi.org/10.1002/ijc.33046
Mc Auley G, Jagannathan J, O’Regan K, Krajewski KM, Hornick JL, Butrynski J, et al. Extraskeletal osteosarcoma: Spectrum of imaging findings. Am J Roentgenol 2012;198:W31-W7. DOI: https://doi.org/10.2214/AJR.11.6927
Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 2012;13:343-57. DOI: https://doi.org/10.1038/nrg3173
Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011;11:726-34. DOI: https://doi.org/10.1038/nrc3130
Li N, Xue W, Yuan H, Dong B, Ding Y, Liu Y, et al. AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis. J Clin Invest 2017;127:1284-302. DOI: https://doi.org/10.1172/JCI91144
Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 2012;81:65-95. DOI: https://doi.org/10.1146/annurev-biochem-051710-134100
Jiang H, Shukla A, Wang X, Chen W-y, Bernstein BE, Roeder RG. Role for dpy-30 in ES cell-fate specification by regulation of H3K4 methylation within bivalent domains. Cell 2011;144:513-25. DOI: https://doi.org/10.1016/j.cell.2011.01.020
Zhang L, Zhang S, Li A, Zhang A, Zhang S, Chen L. DPY30 is required for the enhanced proliferation, motility and epithelial-mesenchymal transition of epithelial ovarian cancer cells. Int J Mol Med 2018;42:3065-72. DOI: https://doi.org/10.3892/ijmm.2018.3869
Yang Z, Augustin J, Chang C, Hu J, Shah K, Chang CW, et al. The DPY30 subunit in SET1/MLL complexes regulates the proliferation and differentiation of hematopoietic progenitor cells. Blood 2014;124:2025-33. DOI: https://doi.org/10.1182/blood-2014-01-549220
Hong ZF, Zhang WQ, Wang SJ, Li SY, Shang J, Liu F, Shen DY. Upregulation of DPY30 promotes cell proliferation and predicts a poor prognosis in cholangiocarcinoma. Biomed Pharmacother 2020;123:109766.
He FX, Zhang LL, Jin PF, Liu DD, Li AH. DPY30 regulates cervical squamous cell carcinoma by mediating epithelial-mesenchymal transition (EMT). Onco Targets Ther 2019;12:7139-47. DOI: https://doi.org/10.2147/OTT.S209315
Lee YJ, Han ME, Baek SJ, Kim SY, Oh SO. Roles of DPY30 in the proliferation and motility of gastric cancer cells. PLoS One 2015;10:e0131863. DOI: https://doi.org/10.1371/journal.pone.0131863
Chen L, Mai W, Chen M, Hu J, Zhuo Z, Lei X, et al. Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin. Pharmacol Res 2017;123:130-42. DOI: https://doi.org/10.1016/j.phrs.2017.07.009
Xue Y, Guo Y, Liu N, Deng Z, Jian Y, Cai H, et al. MicroRNA-22-3p targeted regulating transcription factor 7-like 2 (TCF7L2) constrains the Wnt/β-catenin pathway and malignant behavior in osteosarcoma. Bioengineered 2022;13:9135-9147. DOI: https://doi.org/10.1080/21655979.2021.2003942
Fan TM, Roberts RD, Lizardo MM. Understanding and modeling metastasis biology to improve therapeutic strategies for combating osteosarcoma progression. Front Oncol 2020;10:13. DOI: https://doi.org/10.3389/fonc.2020.00013
He J, Zhang W, Zhou X, Yan W, Wang Z. Aloin induced apoptosis by enhancing autophagic flux through the PI3K/AKT axis in osteosarcoma. Chin Med 2021;16:123. DOI: https://doi.org/10.1186/s13020-021-00520-4
Li H, Shen X, Ma M, Liu W, Yang W, Wang P, et al. ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway. J Exp Clin Cancer Res 2021;40:1-16. DOI: https://doi.org/10.1186/s13046-021-02146-8
Tang H-y, Guo J-q, Sang B-t, Cheng J-n, Wu X-m. PDGFRβ modulates aerobic glycolysis in osteosarcoma HOS cells via the PI3K/AKT/mTOR/c-Myc pathway. Biochem Cell Biol 2022;100:75-84. DOI: https://doi.org/10.1139/bcb-2021-0305
Shi Z, Wang K, Xing Y, Yang X. CircNRIP1 encapsulated by bone marrow mesenchymal stem cell-derived extracellular vesicles aggravates osteosarcoma by modulating the miR-532-3p/AKT3/PI3K/AKT axis. Front Oncol 2021;11:658139. DOI: https://doi.org/10.3389/fonc.2021.658139
Mirabello L, Troisi RJ, Savage SA. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer 2009;125:229-34. DOI: https://doi.org/10.1002/ijc.24320
Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004. Cancer 2009;115:1531-43. DOI: https://doi.org/10.1002/cncr.24121
Collins M, Wilhelm M, Conyers R, Herschtal A, Whelan J, Bielack S, et al. Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol 2013;31:2303-12. DOI: https://doi.org/10.1200/JCO.2012.43.8598
Bernthal NM, Federman N, Eilber FR, Nelson SD, Eckardt JJ, Eilber FC, et al. Long‐term results (> 25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high‐grade, operable osteosarcoma. Cancer 2012;118:5888-93. DOI: https://doi.org/10.1002/cncr.27651
Gill J, Ahluwalia MK, Geller D, Gorlick R. New targets and approaches in osteosarcoma. Pharmacol Ther 2013;137:89-99. DOI: https://doi.org/10.1016/j.pharmthera.2012.09.003
Klein MJ, Siegal GP. Osteosarcoma: Anatomic and histologic variants. Am J Clin Pathol 2006;125:555-81. DOI: https://doi.org/10.1309/UC6KQHLD9LV2KENN
Hong Z-F, Zhang W-Q, Wang S-J, Li S-Y, Shang J, Liu F, et al. Upregulation of DPY30 promotes cell proliferation and predicts a poor prognosis in cholangiocarcinoma. Biomed Pharmacother 2020;123:109766. DOI: https://doi.org/10.1016/j.biopha.2019.109766
Liu Q, Yang H, Hua H. Overexpression of miR-493-3p suppresses ovarian cancer cell proliferation, migration and invasion through downregulating DPY30. Reprod Biol 2022;22:100610. DOI: https://doi.org/10.1016/j.repbio.2022.100610
Yang Q, Jiang W, Hou P. Emerging role of PI3K/AKT in tumor-related epigenetic regulation. Semin Cancer Biol 2019;59:112-24. DOI: https://doi.org/10.1016/j.semcancer.2019.04.001
Spangle JM, Roberts TM, Zhao JJ. The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim Biophys Acta Rev Cancer 2017;1868:123-31. DOI: https://doi.org/10.1016/j.bbcan.2017.03.002
Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 2005;11:2875-8. DOI: https://doi.org/10.1158/1078-0432.CCR-04-2142
Knobbe CB, Trampe-Kieslich A, Reifenberger G. Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathol Appl Neurobiol 2005;31:486-90. DOI: https://doi.org/10.1111/j.1365-2990.2005.00660.x
Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 2005;65:10669-73. DOI: https://doi.org/10.1158/0008-5472.CAN-05-2620
Zhang J, Yu XH, Yan YG, Wang C, Wang WJ. PI3K/Akt signaling in osteosarcoma. Clin Chim Acta 2015;444:182-92. DOI: https://doi.org/10.1016/j.cca.2014.12.041
Soghli N, Ferns GA, Sadeghsoltani F, Qujeq D, Yousefi T, Vaghari-Tabari M. MicroRNAs and osteosarcoma: Potential targets for inhibiting metastasis and increasing chemosensitivity. Biochem Pharmacol 2022;201:115094. DOI: https://doi.org/10.1016/j.bcp.2022.115094
Zhang A, He S, Sun X, Ding L, Bao X, Wang N. Wnt5a promotes migration of human osteosarcoma cells by triggering a phosphatidylinositol-3 kinase/Akt signals. Cancer Cell Int 2014;14:15. DOI: https://doi.org/10.1186/1475-2867-14-15

Ethics Approval

This study was approved by the Institute Research Ethics Committee of Yantaishan Hospital (no. 2018036), The animal use protocol has been reviewed and approved by the Animal Care and Use Ethical Committee of Yantaishan Hospital (no. 202106003)

How to Cite

Cheng, G. ., An, F., Cao, Z., Zheng, M. ., Zhao, Z. ., & Wu, H. (2022). DPY30 promotes the growth and survival of osteosarcoma cell by regulating the PI3K/AKT signal pathway. European Journal of Histochemistry, 67(1). https://doi.org/10.4081/ejh.2023.3413