Journal of Shanghai Jiao Tong University (Medical Science) >

2021 , Vol. 41 >Issue 4: 427 - 433

DOI: https://doi.org/10.3969/j.issn.1674-8115.2021.04.003

Basic research

Molecular mechanism of apoptosis-inducing factor regulated by FBXO22 and its role in cancer cell apoptosis

  • Meng-di LIU ,
  • Yi-lian PAN ,
  • Xiao-na ZHU ,
  • Shuo YANG ,
  • Qian YANG ,
  • Yun YU
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  • 1.Molecular Medicine Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    2.Department of Reproductive Genetics, International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
    3.Department of Obstetrics, International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China

Received date: 2020-07-13

  Online published: 2021-05-14

Supported by

National Natural Science Foundation of China(81772936);Foundation of International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine(GFY5809);Innovative Research Team of High-Level Local Universities in Shanghai(SSMU-ZDCX20180800)

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Abstract

Objective

·To explore the substrate of F-box only protein 22 (FBXO22) and its mechanism, and further study the role of FBXO22 in cancer cell apoptosis.

Methods

·The interaction protein of FBXO22, namely apoptosis-inducing factor (AIF), was searched and identified by immunoprecipitation (IP)-coupled liquid chromatograph mass spectrometer/mass spectrometer (LC-MS/MS) technology. The effect of FBXO22 on ubiquitination of AIF was detected by ubiquitin modification assay under denatured conditions. Short hairpin RNA (shRNA) knockdown FBXO22 and overexpression FBXO22 were used to detect the expression of AIF. The effect of FBXO22 knockdown or overexpression on apoptosis of colon cancer cells was detected by flow cytometry.

Results

·IP-coupled LC-MS/MS technology showed that FBXO22 could interact with AIF, and ubiquitin modification assay under denaturing conditions showed that FBXO22 could mediate ubiquitination of AIF. Knockdown of FBXO22 could up-regulate the level of AIF, while overexpression of FBXO22 could down-regulate the level of AIF. The results of flow cytometry showed that knockdown of FBXO22 could promote the apoptosis of colon cancer cells induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), while overexpression of FBXO22 could inhibit the apoptosis of colon cancer cells induced by MNNG.

Conclusion

· FBXO22 regulates AIF-mediated apoptosis of colon cancer cells by ubiquitination and degradation of AIF.

Key words： F-box only protein 22 (FBOX22); apoptosis-inducing factor (AIF); ubiquitination modification; cell apoptosis

Cite this article

Meng-di LIU , Yi-lian PAN , Xiao-na ZHU , Shuo YANG , Qian YANG , Yun YU . Molecular mechanism of apoptosis-inducing factor regulated by FBXO22 and its role in cancer cell apoptosis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2021 , 41(4) : 427 -433 . DOI: 10.3969/j.issn.1674-8115.2021.04.003

References

1 Nandi D, Tahiliani P, Kumar A, et al. The ubiquitin-proteasome system[J]. J Biosci, 2006, 31(1): 137-155.
2 Tang Q, Wu P, Chen H, et al. Pleiotropic roles of the ubiquitin-proteasome system during viral propagation[J]. Life Sci, 2018, 207: 350-354.
3 Kitagawa K, Kitagawa M. The SCF-type E3 ubiquitin ligases as cancer targets[J]. Curr Cancer Drug Targets, 2016, 16(2): 119-129.
4 Jin J, Cardozo T, Lovering RC, et al. Systematic analysis and nomenclature of mammalian F-box proteins[J]. Genes Dev, 2004, 18(21): 2573-2580.
5 Vrba L, Junk DJ, Novak P, et al. p53 induces distinct epigenetic states at its direct target promoters[J]. BMC Genomics, 2008, 9: 486.
6 Johmura Y, Sun J, Kitagawa K, et al. SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence[J]. Nat Commun, 2016, 7: 10574.
7 Tian X, Dai S, Sun J, et al. F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression[J]. Oncotarget, 2015, 6(26): 22767-22775.
8 Sun R, Xie HY, Qian JX, et al. FBXO22 possesses both protumorigenic and antimetastatic roles in breast cancer progression[J]. Cancer Res, 2018, 78(18): 5274-5286.
9 Bai J, Wu K, Cao M, et al. SCF FBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis[J]. Proceedings of the National Academy of Sciences, 2019, 116(10):201820990.
10 Guo F, Liu J, Han X, et al. FBXO22 suppresses metastasis in human renal cell carcinoma via inhibiting MMP-9-mediated migration and invasion and VEGF-mediated angiogenesis[J]. Int J Biol Sci, 2019, 15(3): 647-656.
11 Lignitto L, LeBoeuf SE, Homer H, et al. Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1[J]. Cell, 2019, 178(2): 316-329.e18.
12 Zhu XN, He P, Zhang L, et al. FBXO22 mediates polyubiquitination and inactivation of LKB1 to promote lung cancer cell growth[J]. Cell Death Dis, 2019, 10(7): 486.
13 Ge MK, Zhang N, Xia L, et al. FBXO22 degrades nuclear PTEN to promote tumorigenesis[J]. Nat Commun, 2020, 11(1): 1720.
14 Moubarak RS, Yuste VJ, Artus C, et al. Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis[J]. Mol Cell Biol, 2007, 27(13): 4844-4862.
15 Yang H, Xie Y, Yang D, et al. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma[J]. Oncotarget, 2017, 8(15): 25310-25322.
16 Jang KH, Do YJ, Son D, et al. AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration[J]. Cell Death Dis, 2017, 8(1): e2526.
17 Joza N, Pospisilik JA, Hangen E, et al. AIF: not just an apoptosis-inducing factor[J]. Ann N Y Acad Sci, 2009, 1171: 2-11.
18 Sevrioukova IF. Apoptosis-inducing factor: structure, function, and redox regulation[J]. Antioxid Redox Signal, 2011, 14(12): 2545-2579.
19 Lewis EM, Wilkinson AS, Davis NY, et al. Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X-linked inhibitor of apoptosis at a residue critical for AIF-mediated chromatin degradation[J]. Biochemistry, 2011, 50(51): 11084-11096.
20 Wilkinson JC, Wilkinson AS, Galbán S, et al. Apoptosis-inducing factor is a target for ubiquitination through interaction with XIAP[J]. Mol Cell Biol, 2008, 28(1): 237-247.
21 Shen SM, Yu Y, Wu YL, et al. Downregulation of ANP32B, a novel substrate of caspase-3, enhances caspase-3 activation and apoptosis induction in myeloid leukemic cells[J]. Carcinogenesis, 2010, 31(3): 419-426.
22 Shen SM, Yu Y, Wu ZX, et al. Apoptosis-inducing factor is a target gene of C/EBPα and participates in adipocyte differentiation[J]. FEBS Lett, 2011, 585(14): 2307-2312.
23 Stambolsky P, Weisz L, Shats I, et al. Regulation of AIF expression by p53[J]. Cell Death Differ, 2006, 13(12): 2140-2149.
24 Pospisilik JA, Knauf C, Joza N, et al. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes[J]. Cell, 2007, 131(3): 476-491.
25 Vahsen N, Candé C, Brière JJ, et al. AIF deficiency compromises oxidative phosphorylation[J]. EMBO J, 2004, 23(23): 4679-4689.
26 Hangen E, Féraud O, Lachkar S, et al. Interaction between AIF and CHCHD4 regulates respiratory chain biogenesis[J]. Mol Cell, 2015, 58(6): 1001-1014.
27 Shen SM, Guo M, Xiong Z, et al. AIF inhibits tumor metastasis by protecting PTEN from oxidation[J]. EMBO Rep, 2015, 16(11): 1563-1580.
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