Research progress of ΔNp63α in malignant tumors_West China Medical Journal

Authors：

GAO Ziping ,  LIANG Weidong , CHEN Hu , SI Yingli , YANG Bo

Department of Cardiothoracic Surgery, the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, P. R. China;

Corresponding author：

LIANG Weidong, Email: qq-53701944@qq.com

Keywords：

ΔNp63α; malignant tumor; therapeutic target

DOI：

10.7507/1002-0179.202209028

Video：

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Abstract Full text Figures/Tables Video References Cited by

Transcription factor p63 originates from p53 protein family and is encoded by TP63 gene. TP63 gene contains two different promoters encoding two proteins, TAp63 and ΔNp63, which can be cleaved to produce p63α, p63β, p63δ and some other subtypes. ΔNp63α is one of the promoters of TP63 gene and acts as a core regulatory factor to regulate gene expression at epigenetic and transcriptional levels. Recent research shows that ΔNp63α abnormal expression can lead to the occurrence of various malignant tumors and reduce the sensitivity of malignant tumors to radiotherapy and chemotherapy. Therefore, ΔNp63α can be used as a diagnostic marker and therapeutic target for malignant tumors. This article reviews the latest research progress of ΔNp63α in the mechanism and drug resistance in malignant tumors.

Citation： GAO Ziping, LIANG Weidong, CHEN Hu, SI Yingli, YANG Bo. Research progress of ΔNp63α in malignant tumors. West China Medical Journal, 2023, 38(2): 304-310. doi: 10.7507/1002-0179.202209028 Copy

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2.	Moses MA, George AL, Sakakibara N, et al. Molecular mechanisms of p63-mediated squamous cancer pathogenesis. Int J Mol Sci, 2019, 20(14): 3590.
3.	Xu J, Li F, Gao Y, et al. E47 upregulates ΔNp63α to promote growth of squamous cell carcinoma. Cell Death Dis, 2021, 12(4): 381.
4.	Anon. Oncogenic Ras/PI3K/Her2 share a common pathway in promoting cancer metastasis via inhibiting expression of p53-related ΔNp63α. Sci Foundat China, 2017, 25(3): 43.
5.	Yi Y, Chen D, Ao J, et al. Metformin promotes AMP-activated protein kinase-independent suppression of ΔNp63α protein expression and inhibits cancer cell viability. J Biol Chem, 2017, 292(13): 5253-5261.
6.	Tran MN, Choi W, Wszolek MF, et al. The p63 protein isoform ΔNp63α inhibits epithelial-mesenchymal transition in human bladder cancer cells: role of MIR-205. J Biol Chem, 2013, 288(5): 3275-3288.
7.	Dang TT, Esparza MA, Maine EA, et al. ΔNp63α promotes breast cancer cell motility through the selective activation of components of the epithelial-to-mesenchymal transition program. Cancer Res, 2015, 75(18): 3925-3935.
8.	Wu G, Osada M, Guo Z, et al. DeltaNp63alpha up-regulates the Hsp70 gene in human cancer. Cancer Res, 2005, 65(3): 758-766.
9.	Huang Y, Chuang A, Hao H, et al. Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells. Cell Death Differ, 2011, 18(7): 1220-1230.
10.	Fisher ML, Balinth S, Mills AA. ΔNp63α in cancer: importance and therapeutic opportunities. Trends Cell Biol, 2022, S0962-8924(22): 00194-5.
11.	Zhou P, Zhang C, Song X, et al. Correction to: ΔNp63α promotes bortezomib resistance via the CYGB-ROS axis in head and neck squamous cell carcinoma. Cell Death Dis, 2022, 13(6): 519.
12.	Fu Y, Tian G, Zhang Z, et al. SYT7 acts as an oncogene and a potential therapeutic target and was regulated by ΔNp63α in HNSCC. Cancer Cell Int, 2021, 21(1): 696.
13.	Hira A, Stacy A, Zhang J, et al. TIP60 mediated regulation of ΔNp63α is associated with Cisplatin resistance. FASEB J, 2022: 36.
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21.	Bisso A, Collavin L, Del Sal G. p73 as a pharmaceutical target for cancer therapy. Curr Pharm Des, 2011, 17(6): 578-590.
22.	Graziano V, De Laurenzi V. Role of p63 in cancer development. Biochim Biophys Acta, 2011, 1816(1): 57-66.
23.	Mangiulli M, Valletti A, Caratozzolo MF, et al. Identification and functional characterization of two new transcriptional variants of the human p63 gene. Nucleic Acids Res, 2009, 37(18): 6092-6104.
24.	Helton ES, Zhu J, Chen X. The unique NH2-terminally deleted (DeltaN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the DeltaN variant of p63. J Biol Chem, 2006, 281(5): 2533-2542.
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26.	Wu G, Nomoto S, HoquE MO, et al. DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res, 2003, 63(10): 2351-2357.
27.	Gallant-Behm CL, Espinosa JM. How does ΔNp63α drive cancer?. Epigenomics, 2013, 5(1): 5-7.
28.	Parsa R, Yang A, McKeon F, et al. Association of p63 with proliferative potential in normal and neoplastic human keratinocytes. J Invest Dermatol, 1999, 113(6): 1099-1105.
29.	Zhou P, Zhang C, Song X, et al. ΔNp63α promotes Bortezomib resistance via the CYGB-ROS axis in head and neck squamous cell carcinoma. Cell Death Dis, 2022, 13(4): 327.
30.	Ratovitski EA. Phospho-ΔNp63α-responsive microRNAs contribute to the regulation of necroptosis in squamous cell carcinoma upon cisplatin exposure. FEBS Lett, 2015, 589(12): 1352-1358.
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33.	Chung J, Lau J, Cheng LS, et al. SATB2 augments ΔNp63α in head and neck squamous cell carcinoma. EMBO Rep, 2010, 11(10): 777-783.
34.	Chen H, Hu K, Xie Y, et al. CDK1 promotes epithelial-mesenchymal transition and migration of head and neck squamous carcinoma cells by repressing ΔNp63α-mediated transcriptional regulation. Int J Mol Sci, 2022, 23(13): 7385.
35.	Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
36.	Balinth S, Fisher ML, Hwangbo Y, et al. EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma. Oncogene, 2022, 41(35): 4130-4144.
37.	Latina A, Viticchiè G, Lena AM, et al. ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer. Oncogene, 2016, 35(12): 1493-1503.
38.	李小婷, 谢春凤, 朱剑云, 等. 莱菔硫烷通过 IL-6/ΔNp63α/Notch 轴抑制慢性香烟暴露诱导的肺癌干细胞特性//营养研究与临床实践—第十四届全国营养科学大会暨第十一届亚太临床营养大会、第二届全球华人营养科学家大会论文摘要汇编. 南京: 中国营养学会, 2019: 258-259.
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1. Campbell JD, Yau C, Bowlby R, et al. Genomic, pathway network, and immunologic features distinguishing squamous carcinomas. Cell Rep, 2018, 23(1): 194-212.e6.
2. Moses MA, George AL, Sakakibara N, et al. Molecular mechanisms of p63-mediated squamous cancer pathogenesis. Int J Mol Sci, 2019, 20(14): 3590.
3. Xu J, Li F, Gao Y, et al. E47 upregulates ΔNp63α to promote growth of squamous cell carcinoma. Cell Death Dis, 2021, 12(4): 381.
4. Anon. Oncogenic Ras/PI3K/Her2 share a common pathway in promoting cancer metastasis via inhibiting expression of p53-related ΔNp63α. Sci Foundat China, 2017, 25(3): 43.
5. Yi Y, Chen D, Ao J, et al. Metformin promotes AMP-activated protein kinase-independent suppression of ΔNp63α protein expression and inhibits cancer cell viability. J Biol Chem, 2017, 292(13): 5253-5261.
6. Tran MN, Choi W, Wszolek MF, et al. The p63 protein isoform ΔNp63α inhibits epithelial-mesenchymal transition in human bladder cancer cells: role of MIR-205. J Biol Chem, 2013, 288(5): 3275-3288.
7. Dang TT, Esparza MA, Maine EA, et al. ΔNp63α promotes breast cancer cell motility through the selective activation of components of the epithelial-to-mesenchymal transition program. Cancer Res, 2015, 75(18): 3925-3935.
8. Wu G, Osada M, Guo Z, et al. DeltaNp63alpha up-regulates the Hsp70 gene in human cancer. Cancer Res, 2005, 65(3): 758-766.
9. Huang Y, Chuang A, Hao H, et al. Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells. Cell Death Differ, 2011, 18(7): 1220-1230.
10. Fisher ML, Balinth S, Mills AA. ΔNp63α in cancer: importance and therapeutic opportunities. Trends Cell Biol, 2022, S0962-8924(22): 00194-5.
11. Zhou P, Zhang C, Song X, et al. Correction to: ΔNp63α promotes bortezomib resistance via the CYGB-ROS axis in head and neck squamous cell carcinoma. Cell Death Dis, 2022, 13(6): 519.
12. Fu Y, Tian G, Zhang Z, et al. SYT7 acts as an oncogene and a potential therapeutic target and was regulated by ΔNp63α in HNSCC. Cancer Cell Int, 2021, 21(1): 696.
13. Hira A, Stacy A, Zhang J, et al. TIP60 mediated regulation of ΔNp63α is associated with Cisplatin resistance. FASEB J, 2022: 36.
14. 陈中, 张嘉玲, 杨歆萍, 等. 抑癌基因 TP53 及新家族成员 TP63 和 TP73 的研究新进展. 内蒙古医科大学学报, 2013, 35(1): 57-62.
15. Jost CA, Marin MC, Kaelin WG Jr. p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature, 1997, 389(6647): 191-194.
16. Dickman S. First p53 relative may be a new tumor suppressor. Science, 1997, 277(5332): 1605-1606.
17. Yang A, Kaghad M, Wang Y, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell, 1998, 2(3): 305-316.
18. Liu H, Zhu C, Xu Z, et al. lncRNA PART1 and MIR17HG as ΔNp63α direct targets regulate tumor progression of cervical squamous cell carcinoma. Cancer Sci, 2020, 111(11): 4129-4141.
19. Dohn M, Zhang S, Chen X. p63alpha and DeltaNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes. Oncogene, 2001, 20(25): 3193-3205.
20. Buhlmann S, Pützer BM. DNp73 a matter of cancer: mechanisms and clinical implications. Biochim Biophys Acta, 2008, 1785(2): 207-216.
21. Bisso A, Collavin L, Del Sal G. p73 as a pharmaceutical target for cancer therapy. Curr Pharm Des, 2011, 17(6): 578-590.
22. Graziano V, De Laurenzi V. Role of p63 in cancer development. Biochim Biophys Acta, 2011, 1816(1): 57-66.
23. Mangiulli M, Valletti A, Caratozzolo MF, et al. Identification and functional characterization of two new transcriptional variants of the human p63 gene. Nucleic Acids Res, 2009, 37(18): 6092-6104.
24. Helton ES, Zhu J, Chen X. The unique NH2-terminally deleted (DeltaN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the DeltaN variant of p63. J Biol Chem, 2006, 281(5): 2533-2542.
25. Fomenkov A, Zangen R, Huang YP, et al. RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage. Cell Cycle, 2004, 3(10): 1285-1295.
26. Wu G, Nomoto S, HoquE MO, et al. DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res, 2003, 63(10): 2351-2357.
27. Gallant-Behm CL, Espinosa JM. How does ΔNp63α drive cancer?. Epigenomics, 2013, 5(1): 5-7.
28. Parsa R, Yang A, McKeon F, et al. Association of p63 with proliferative potential in normal and neoplastic human keratinocytes. J Invest Dermatol, 1999, 113(6): 1099-1105.
29. Zhou P, Zhang C, Song X, et al. ΔNp63α promotes Bortezomib resistance via the CYGB-ROS axis in head and neck squamous cell carcinoma. Cell Death Dis, 2022, 13(4): 327.
30. Ratovitski EA. Phospho-ΔNp63α-responsive microRNAs contribute to the regulation of necroptosis in squamous cell carcinoma upon cisplatin exposure. FEBS Lett, 2015, 589(12): 1352-1358.
31. 周鹏. ΔNp63α 在头颈鳞状细胞癌中对硼替佐米耐药的作用及机制研究. 上海: 中国人民解放军海军军医大学, 2020.
32. 周梦燕. ΔNp63α 对下咽鳞状细胞癌上皮—间质转化的作用研究. 上海: 第二军医大学, 2017.
33. Chung J, Lau J, Cheng LS, et al. SATB2 augments ΔNp63α in head and neck squamous cell carcinoma. EMBO Rep, 2010, 11(10): 777-783.
34. Chen H, Hu K, Xie Y, et al. CDK1 promotes epithelial-mesenchymal transition and migration of head and neck squamous carcinoma cells by repressing ΔNp63α-mediated transcriptional regulation. Int J Mol Sci, 2022, 23(13): 7385.
35. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
36. Balinth S, Fisher ML, Hwangbo Y, et al. EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma. Oncogene, 2022, 41(35): 4130-4144.
37. Latina A, Viticchiè G, Lena AM, et al. ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer. Oncogene, 2016, 35(12): 1493-1503.
38. 李小婷, 谢春凤, 朱剑云, 等. 莱菔硫烷通过 IL-6/ΔNp63α/Notch 轴抑制慢性香烟暴露诱导的肺癌干细胞特性//营养研究与临床实践—第十四届全国营养科学大会暨第十一届亚太临床营养大会、第二届全球华人营养科学家大会论文摘要汇编. 南京: 中国营养学会, 2019: 258-259.
39. 姜叶. △Np63α/Notch 轴介导莱菔硫烷干预慢性吸烟暴露诱导人支气管上皮细胞向肺癌干细胞转化的机制研究. 南京: 南京医科大学, 2017.
40. Thépot A, Hautefeuille A, Cros MP, et al. Intraepithelial p63-dependent expression of distinct components of cell adhesion complexes in normal esophageal mucosa and squamous cell carcinoma. Int J Cancer, 2010, 127(9): 2051-2062.
41. Jiang YY, Jiang Y, Li CQ, et al. TP63, SOX2, and KLF5 establish a core regulatory circuitry that controls epigenetic and transcription patterns in esophageal squamous cell carcinoma cell lines. Gastroenterology, 2020, 159(4): 1311-1327.
42. Lee KB, Ye S, Park MH, et al. p63-Mediated activation of the β-catenin/c-Myc signaling pathway stimulates esophageal squamous carcinoma cell invasion and metastasis. Cancer Lett, 2014, 353(1): 124-132.
43. Chen Y, Wang MH, Wu JY, et al. ΔNp63α mediates sulforaphane suppressed colorectal cancer stem cell properties through transcriptional regulation of Nanog/Oct4/Sox2. J Nutr Biochem, 2022, 107: 109067.
44. Wang H, Liu Z, Li J, et al. ΔNp63α mediates proliferation and apoptosis in human gastric cancer cells by the regulation of GATA-6. Neoplasma, 2012, 59(4): 416-423.
45. Di Giacomo V, Tian TV, Mas A, et al. ΔNp63α promotes adhesion of metastatic prostate cancer cells to the bone through regulation of CD82. Oncogene, 2017, 36(31): 4381-4392.
46. Zhou Y, Liu H, Wang J, et al. ΔNp63α exerts antitumor functions in cervical squamous cell carcinoma. Oncogene, 2020, 39(4): 905-921.
47. Nekulova M, Holcakova J, Gu X, et al. ΔNp63α expression induces loss of cell adhesion in triple-negative breast cancer cells. BMC Cancer, 2016, 16(1): 782.
48. Minion LE, Tewari KS. Cervical cancer. State of the science: from angiogenesis blockade to checkpoint inhibition. Gynecol Oncol, 2018, 148(3): 609-621.
49. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
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