Research progress of valosin-containing protein in tumors_West China Medical Journal

Authors：

 ZHAO Ji’ou

Faculty of Nursing, Jiangsu Food and Pharmaceutical Science College, Huai’an, Jiangsu 223003, P. R. China;

Corresponding?author：

ZHAO Ji’ou, Email: m15162102018@163.com

Keywords：

Valosin-containing protein; Cellular homeostasis; Ubiquitin; Tumors

DOI：

10.7507/1002-0179.202002178

Video：

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Abstract Full text Figures/Tables Video References Cited by

Valosin-containing protein is a membrane-bound protein that is highly conserved and widely existed in cells. Valosin-containing protein and it’s cofactors jointly participate in various cell functions such as protein degradation, gene replication, and cell cycle regulation, which maintain cellular homeostasis. Valosin-containing protein also exists in tumor cells, and its expression is closely related to the occurrence and development of tumors, but the specific mechanism needs to be further clarified. The application of valosin-containing protein inhibitors in tumor treatment has been continuously and in-depth researched. This article will explore several aspects of the molecular basis of valosin-containing protein, valosin-containing protein and cell homeostasis, tumors, and targeted therapy with valosin-containing protein. It aims to provide a certain basis for the clinical application of valosin-containing protein inhibitors.

Citation： ZHAO Ji’ou. Research progress of valosin-containing protein in tumors. West China Medical Journal, 2021, 36(12): 1788-1792. doi: 10.7507/1002-0179.202002178 Copy

1.	Xia D, Tang WK, Ye Y. Structure and function of the AAA+ ATPase p97/Cdc48p. Gene, 2016, 583(1): 64-77.
2.	Mengel D, Librizzi D, Schoser B, et al. Inclusion body myopathy, paget’s disease, and fronto-temporal dementia: a VCP-related multi-systemic proteinopathy. Fortschr Neurol Psychiatr, 2018, 86(7): 434-438.
3.	Banerjee S, Bartesaghi A, Merk A, et al. 2. 3 ? resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science, 2016, 351(6275): 871-875.
4.	Meyer H, Bug M, Bremer S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol, 2012, 14(2): 117-123.
5.	Fessart D, Marza E, Taouji S, et al. P97/CDC-48: proteostasis control in tumor cell biology. Cancer Lett, 2013, 337(1): 26-34.
6.	Haines DS. p97-containing complexes in proliferation control and cancer: emerging culprits or guilt by association?. Genes Cancer, 2010, 1(7): 753-763.
7.	Arumughan A, Roske Y, Barth C, et al. Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers. Nat Commun, 2016, 7: 13047.
8.	Le LT, Kang W, Kim JY, et al. Structural details of Ufd1 binding to p97 and their functional implications in ER-associated degradation. PLoS One, 2016, 11(9): e0163394.
9.	Bodnar NO, Kim KH, Ji Z, et al. Structure of the Cdc48 ATPase with its ubiquitin-binding cofactor Ufd1-Npl4. Nat Struct Mol Biol, 2018, 25(7): 616-622.
10.	Jain BP. An overview of unfolded protein response signaling and its role in cancer. Cancer Biother Radiopharm, 2017, 32(8): 275-281.
11.	Meusser B, Hirsch C, Jarosch E, et al. ERAD: the long road to destruction. Nat Cell Biol, 2005, 7(8): 766-772.
12.	Taylor EB, Rutter J. Mitochondrial quality control by the ubiquitin-proteasome system. Biochem Soc Trans, 2011, 39(5): 1509-1513.
13.	Karbowski M, Youle RJ. Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Curr Opin Cell Biol, 2011, 23(4): 476-482.
14.	Papadopoulos C, Kirchner P, Bug M, et al. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J, 2017, 36(2): 135-150.
15.	Tresse E, Salomons FA, Vesa J, et al. VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy, 2010, 6(2): 217-227.
16.	Ramadan K, Halder S, Wiseman K, et al. Strategic role of the ubiquitin-dependent segregase p97 (VCP or Cdc48) in DNA replication. Chromosoma, 2017, 126(1): 17-32.
17.	van den Boom J, Wolf M, Weimann L, et al. VCP/p97 extracts sterically trapped Ku70/80 rings from DNA in double-strand break repair. Mol Cell, 2016, 64(1): 189-198.
18.	Maric M, Mukherjee P, Tatham MH, et al. Ufd1-Npl4 recruit Cdc48 for disassembly of ubiquitylated CMG helicase at the end of chromosome replication. Cell Rep, 2017, 18(13): 3033-3042.
19.	Yamamoto S, Tomita Y, Uruno T, et al. Increased expression of valosin-containing protein (p97) is correlated with disease recurrence in follicular thyroid cancer. Ann Surg Oncol, 2005, 12(11): 925-934.
20.	Meyer MF, Seuthe IM, Drebber U, et al. Valosin-containing protein (VCP/p97)-expression correlates with prognosis of HPV- negative oropharyngeal squamous cell carcinoma (OSCC). PLoS One, 2014, 9(12): e114170.
21.	Yamamoto S, Tomita Y, Hoshida Y, et al. Expression level of valosin-containing protein (p97) is associated with prognosis of esophageal carcinoma. Clin Cancer Res, 2004, 11(7): 5558-5565.
22.	Duscharla D, Reddy Kami Reddy K, Dasari C, et al. Interleukin-6 induced overexpression of valosin-containing protein (VCP)/p97 is associated with androgen-independent prostate cancer (AIPC) progression. J Cell Physiol, 2018, 233(10): 7148-7164.
23.	Valle CW, Min T, Bodas M, et al. Critical role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma. PLoS One, 2011, 6(12): e29073.
24.	Liu Y, Hei Y, Shu Q, et al. VCP/p97, down-regulated by microRNA-129-5p, could regulate the progression of hepatocellular carcinoma. PLoS One, 2012, 7(4): e35800.
25.	Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 2008, 321(5897): 1801-1806.
26.	Le Moigne R, Aftab BT, Djakovic S, et al. The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma. Mol Cancer Ther, 2017, 16(11): 2375-2386.
27.	Bastola P, Wang F, Schaich MA, et al. Specific mutations in the D1-D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors. Cell Death Discov, 2017, 3: 17065.
28.	Vekaria PH, Kumar A, Subramaniam D, et al. Functional cooperativity of p97 and histone deacetylase 6 in mediating DNA repair in mantle cell lymphoma cells. Leukemia, 2019, 33(7): 1675-1686.
29.	Bao D, Cheng C, Lan X, et al. Regulation of p53wt glioma cell proliferation by androgen receptor-mediated inhibition of small VCP/p97-interacting protein expression. Oncotarget, 2017, 8(14): 23142-23154.
30.	Tegowski M, Baldwin A. Noncanonical NF-κB in cancer. Biomedicines, 2018, 6(2): 66.
31.	Li JM, Wu H, Zhang W, et al. The p97-UFD1L-NPL4 protein complex mediates cytokine-induced IκBα proteolysis. Mol Cell Biol, 2014, 34(3): 335-347.
32.	Zhang Z, Wang Y, Li C, et al. The transitional endoplasmic reticulum ATPase p97 regulates the alternative nuclear factor NF-κB signaling via partial degradation of the NF-κB subunit p100. J Biol Chem, 2015, 290(32): 19558-19568.
33.	Alexandru G, Graumann J, Smith GT, et al. UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover. Cell, 2008, 134(5): 804-816.
34.	Bandau S, Knebel A, Gage ZO, et al. UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation. BMC Biol, 2012, 10: 36.
35.	Vandermoere F, El Yazidi-Belkoura I, Slomianny C, et al. The valosin-containing protein (VCP) is a target of Akt signaling required for cell survival. J Biol Chem, 2006, 281(20): 14307-14313.
36.	Flack JE, Mieszczanek J, Novcic N, et al. Wnt-dependent inactivation of the groucho/TLE co-repressor by the HECT E3 ubiquitin ligase Hyd/UBR5. Mol Cell, 2017, 67(2): 181-193.e5.
37.	Fu X, Ng C, Feng D, et al. Cdc48p is required for the cell cycle commitment point at start via degradation of the G1-CDK inhibitor Far1p. J Cell Biol, 2003, 163(1): 21-26.
38.	Parisi E, Yahya G, Flores A, et al. Cdc48/p97 segregase is modulated by cyclin-dependent kinase to determine cyclin fate during G1 progression. EMBO J, 2018, 37(16): e98724.
39.	Bastola P, Neums L, Schoenen FJ, et al. VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with salubrinal. Mol Oncol, 2016, 10(10): 1559-1574.
40.	Gugliotta G, Sudo M, Cao Q, et al. Valosin-containing protein/p97 as a novel therapeutic target in acute lymphoblastic leukemia. Neoplasia, 2017, 19(10): 750-761.
41.	Zhao Z, Wu M, Zhang X, et al. CB-5083, an inhibitor of p97, suppresses osteosarcoma growth and stem cell properties by altering protein homeostasis. Am J Transl Res, 2020, 12(6): 2956-2967.
42.	Chou TF, Li K, Frankowski KJ, et al. Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. ChemMedChem, 2013, 8(2): 297-312.
43.	Magnaghi P, D’Alessio R, Valsasina B, et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat Chem Biol, 2013, 9(9): 548-556.
44.	Zhang J, Hu Y, Hau R, et al. Identification of NMS-873, an allosteric and specific p97 inhibitor, as a broad antiviral against both influenza A and B viruses. Eur J Pharm Sci, 2019, 133: 86-94.
45.	Skrott Z, Mistrik M, Andersen KK, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature, 2017, 552(7684): 194-199.

1. Xia D, Tang WK, Ye Y. Structure and function of the AAA+ ATPase p97/Cdc48p. Gene, 2016, 583(1): 64-77.
2. Mengel D, Librizzi D, Schoser B, et al. Inclusion body myopathy, paget’s disease, and fronto-temporal dementia: a VCP-related multi-systemic proteinopathy. Fortschr Neurol Psychiatr, 2018, 86(7): 434-438.
3. Banerjee S, Bartesaghi A, Merk A, et al. 2. 3 ? resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science, 2016, 351(6275): 871-875.
4. Meyer H, Bug M, Bremer S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol, 2012, 14(2): 117-123.
5. Fessart D, Marza E, Taouji S, et al. P97/CDC-48: proteostasis control in tumor cell biology. Cancer Lett, 2013, 337(1): 26-34.
6. Haines DS. p97-containing complexes in proliferation control and cancer: emerging culprits or guilt by association?. Genes Cancer, 2010, 1(7): 753-763.
7. Arumughan A, Roske Y, Barth C, et al. Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers. Nat Commun, 2016, 7: 13047.
8. Le LT, Kang W, Kim JY, et al. Structural details of Ufd1 binding to p97 and their functional implications in ER-associated degradation. PLoS One, 2016, 11(9): e0163394.
9. Bodnar NO, Kim KH, Ji Z, et al. Structure of the Cdc48 ATPase with its ubiquitin-binding cofactor Ufd1-Npl4. Nat Struct Mol Biol, 2018, 25(7): 616-622.
10. Jain BP. An overview of unfolded protein response signaling and its role in cancer. Cancer Biother Radiopharm, 2017, 32(8): 275-281.
11. Meusser B, Hirsch C, Jarosch E, et al. ERAD: the long road to destruction. Nat Cell Biol, 2005, 7(8): 766-772.
12. Taylor EB, Rutter J. Mitochondrial quality control by the ubiquitin-proteasome system. Biochem Soc Trans, 2011, 39(5): 1509-1513.
13. Karbowski M, Youle RJ. Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Curr Opin Cell Biol, 2011, 23(4): 476-482.
14. Papadopoulos C, Kirchner P, Bug M, et al. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J, 2017, 36(2): 135-150.
15. Tresse E, Salomons FA, Vesa J, et al. VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy, 2010, 6(2): 217-227.
16. Ramadan K, Halder S, Wiseman K, et al. Strategic role of the ubiquitin-dependent segregase p97 (VCP or Cdc48) in DNA replication. Chromosoma, 2017, 126(1): 17-32.
17. van den Boom J, Wolf M, Weimann L, et al. VCP/p97 extracts sterically trapped Ku70/80 rings from DNA in double-strand break repair. Mol Cell, 2016, 64(1): 189-198.
18. Maric M, Mukherjee P, Tatham MH, et al. Ufd1-Npl4 recruit Cdc48 for disassembly of ubiquitylated CMG helicase at the end of chromosome replication. Cell Rep, 2017, 18(13): 3033-3042.
19. Yamamoto S, Tomita Y, Uruno T, et al. Increased expression of valosin-containing protein (p97) is correlated with disease recurrence in follicular thyroid cancer. Ann Surg Oncol, 2005, 12(11): 925-934.
20. Meyer MF, Seuthe IM, Drebber U, et al. Valosin-containing protein (VCP/p97)-expression correlates with prognosis of HPV- negative oropharyngeal squamous cell carcinoma (OSCC). PLoS One, 2014, 9(12): e114170.
21. Yamamoto S, Tomita Y, Hoshida Y, et al. Expression level of valosin-containing protein (p97) is associated with prognosis of esophageal carcinoma. Clin Cancer Res, 2004, 11(7): 5558-5565.
22. Duscharla D, Reddy Kami Reddy K, Dasari C, et al. Interleukin-6 induced overexpression of valosin-containing protein (VCP)/p97 is associated with androgen-independent prostate cancer (AIPC) progression. J Cell Physiol, 2018, 233(10): 7148-7164.
23. Valle CW, Min T, Bodas M, et al. Critical role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma. PLoS One, 2011, 6(12): e29073.
24. Liu Y, Hei Y, Shu Q, et al. VCP/p97, down-regulated by microRNA-129-5p, could regulate the progression of hepatocellular carcinoma. PLoS One, 2012, 7(4): e35800.
25. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 2008, 321(5897): 1801-1806.
26. Le Moigne R, Aftab BT, Djakovic S, et al. The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma. Mol Cancer Ther, 2017, 16(11): 2375-2386.
27. Bastola P, Wang F, Schaich MA, et al. Specific mutations in the D1-D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors. Cell Death Discov, 2017, 3: 17065.
28. Vekaria PH, Kumar A, Subramaniam D, et al. Functional cooperativity of p97 and histone deacetylase 6 in mediating DNA repair in mantle cell lymphoma cells. Leukemia, 2019, 33(7): 1675-1686.
29. Bao D, Cheng C, Lan X, et al. Regulation of p53wt glioma cell proliferation by androgen receptor-mediated inhibition of small VCP/p97-interacting protein expression. Oncotarget, 2017, 8(14): 23142-23154.
30. Tegowski M, Baldwin A. Noncanonical NF-κB in cancer. Biomedicines, 2018, 6(2): 66.
31. Li JM, Wu H, Zhang W, et al. The p97-UFD1L-NPL4 protein complex mediates cytokine-induced IκBα proteolysis. Mol Cell Biol, 2014, 34(3): 335-347.
32. Zhang Z, Wang Y, Li C, et al. The transitional endoplasmic reticulum ATPase p97 regulates the alternative nuclear factor NF-κB signaling via partial degradation of the NF-κB subunit p100. J Biol Chem, 2015, 290(32): 19558-19568.
33. Alexandru G, Graumann J, Smith GT, et al. UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover. Cell, 2008, 134(5): 804-816.
34. Bandau S, Knebel A, Gage ZO, et al. UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation. BMC Biol, 2012, 10: 36.
35. Vandermoere F, El Yazidi-Belkoura I, Slomianny C, et al. The valosin-containing protein (VCP) is a target of Akt signaling required for cell survival. J Biol Chem, 2006, 281(20): 14307-14313.
36. Flack JE, Mieszczanek J, Novcic N, et al. Wnt-dependent inactivation of the groucho/TLE co-repressor by the HECT E3 ubiquitin ligase Hyd/UBR5. Mol Cell, 2017, 67(2): 181-193.e5.
37. Fu X, Ng C, Feng D, et al. Cdc48p is required for the cell cycle commitment point at start via degradation of the G1-CDK inhibitor Far1p. J Cell Biol, 2003, 163(1): 21-26.
38. Parisi E, Yahya G, Flores A, et al. Cdc48/p97 segregase is modulated by cyclin-dependent kinase to determine cyclin fate during G1 progression. EMBO J, 2018, 37(16): e98724.
39. Bastola P, Neums L, Schoenen FJ, et al. VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with salubrinal. Mol Oncol, 2016, 10(10): 1559-1574.
40. Gugliotta G, Sudo M, Cao Q, et al. Valosin-containing protein/p97 as a novel therapeutic target in acute lymphoblastic leukemia. Neoplasia, 2017, 19(10): 750-761.
41. Zhao Z, Wu M, Zhang X, et al. CB-5083, an inhibitor of p97, suppresses osteosarcoma growth and stem cell properties by altering protein homeostasis. Am J Transl Res, 2020, 12(6): 2956-2967.
42. Chou TF, Li K, Frankowski KJ, et al. Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. ChemMedChem, 2013, 8(2): 297-312.
43. Magnaghi P, D’Alessio R, Valsasina B, et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat Chem Biol, 2013, 9(9): 548-556.
44. Zhang J, Hu Y, Hau R, et al. Identification of NMS-873, an allosteric and specific p97 inhibitor, as a broad antiviral against both influenza A and B viruses. Eur J Pharm Sci, 2019, 133: 86-94.
45. Skrott Z, Mistrik M, Andersen KK, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature, 2017, 552(7684): 194-199.

West China Medical Journal

Research progress of valosin-containing protein in tumors

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