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HECTD2 Represses Cell Proliferation in Colorectal Cancer through Driving Ubiquitination and Degradation of LPCAT1

  • MOLECULAR CELL BIOLOGY
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Abstract

Colorectal cancer (CRC) is a malignancy featured by a poor overall survival and a high recurrence rate, whereas the biomarkers for CRC remain to be investigated. Herein, it was found that lysophosphatidylcholine acyltransferase 1 (LPCAT1) was highly expressed in CRC, and LPCAT1 overexpression significantly promoted CRC cell proliferation, while it was reversed by LPCAT1 depletion. In addition, HECT domain-containing 2 (HECTD2) protein was determined as a post-translational mediator of LPCAT1 because HECTD2 co-immunoprecipitated with high ubiquitinated LPCAT1. Furthermore, upregulated LPCAT1 rescued the impairment of CRC cell proliferation caused by HECTD2 overexpression. In conclusion, our findings supported HECTD2/LPCAT1 axis as a potential prognostic biomarker in CRC.

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REFERENCES

  1. Erratum: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 70, 313 (2020).

  2. Feng M., Zhao Z., Yang M., Ji J., Zhu D. 2021. T-cell-based immunotherapy in colorectal cancer. Cancer Lett. 498, 201‒209.

    Article  CAS  Google Scholar 

  3. Barbosa A., Savage D., Siniossoglou S. 2015. Lipid droplet-organelle interactions: Emerging roles in lipid metabolism. Curr. Opin. Cell Biol 35, 91‒97.

    Article  CAS  Google Scholar 

  4. Shindou H., Hishikawa D., Harayama T., Yuki K., Shimizu T. 2009. Recent progress on acyl CoA: Lysophospholipid acyltransferase research. J. Lipid Res. S46‒S51.

  5. Lin S., Ikegami M., Moon C., Naren A. Shannon J. 2015. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) specifically interacts with phospholipid transfer protein StarD10 to facilitate surfactant phospholipid trafficking in alveolar type II cells. J. Biol. Chem. 290, 18559‒18574.

    Article  CAS  Google Scholar 

  6. Dai X., Zhang H., Han J., He Y., Zhang Y., Qi Y., Pang J.J. 2016. Effects of subretinal gene transfer at different time points in a mouse model of retinal degeneration. PLoS One. 11, e0156542.

    Article  Google Scholar 

  7. Okubo M., Yamanaka H., Kobayashi K., Kanda H., Dai Y., Noguchi K. 2012. Up-regulation of platelet-activating factor synthases and its receptor in spinal cord contribute to development of neuropathic pain following peripheral nerve injury. Mol. Pain. 8, 8.

    Article  CAS  Google Scholar 

  8. Zhao T., Zhang Y., Ma X., Wei L., Hou Y., Sun R., Jiang J. 2021. Elevated expression of LPCAT1 predicts a poor prognosis and is correlated with the tumour microenvironment in endometrial cancer. Cancer Cell Int. 21, 269.

    Article  CAS  Google Scholar 

  9. Han C., Yu G., Mao Y., Song S., Li L., Zhou L., Wang Z., Liu Y., Li M., Xu B. 2020. LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production. PLoS One. 15, e0240801.

    Article  CAS  Google Scholar 

  10. Wei C., Dong X., Lu H., Tong F., Chen L., Zhang R., Dong J., Hu Y., Wu G., Dong X. 2019. LPCAT1 promotes brain metastasis of lung adenocarcinoma by up-regulating PI3K/AKT/MYC pathway. J. Exp. Clin. Cancer Res. 38, 95.

    Article  Google Scholar 

  11. Mansilla F., da Costa K., Wang S., Kruhøffer M., Lewin T., Orntoft T., Coleman R., Birkenkamp-Demtröder K. 2009. Lysophosphatidylcholine acyltransferase 1 (LPCAT1. overexpression in human colorectal cancer. J. Mol. Med. Berl. 87, 85‒97.

    Article  CAS  Google Scholar 

  12. Deribe Y.L., Pawson T. Dikic I. 2010. Post-translational modifications in signal integration. Nat. Struct. Mol. Biol. 17, 666.

    Article  CAS  Google Scholar 

  13. Schwartz A. Ciechanover A. 2009. Targeting proteins for destruction by the ubiquitin system: Implications for human pathobiology. Annu. Rev. Pharmacol. Toxicol. 49, 73‒96.

    Article  CAS  Google Scholar 

  14. Jones D., Crowe E., Stevens T.A. Candido E.P.M. 2001. Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: Ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins. Genome Biol. 3(1), RESEARCH0002. https://doi.org/10.1186/gb-2001-3-1-research0002

  15. Wójcik C., DeMartino G.N. 2003. Intracellular localization of proteasomes. Int. J. Biochem. Cell Biol. 35, 579‒589.

    Article  Google Scholar 

  16. Song Y., Wu C., Wu K., Han Q., Miao X., Ma D., Leung C. 2021. Ubiquitination regulators discovered by virtual screening for the treatment of cancer. Front. Cell Dev. Biol. 9, 665646.

    Article  Google Scholar 

  17. Xu Y., Wang C., Jiang X., Zhang Y., Su H., Jiang J., Ren H., Qiu X. 2021. KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway. Cell Death Dis. 12, 556.

    Article  CAS  Google Scholar 

  18. Castro-Gonzalez S., Simpson S., Shi Y., Chen Y., Benjamin J., Serra-Moreno R. 2021. HIV Nef-mediated ubiquitination of BCL2: Implications in autophagy and apoptosis. Front. Immunol. 12, 682624.

    Article  CAS  Google Scholar 

  19. Liu J., Li X., Zhou G., Zhang Y., Sang Y., Wang J., Li Y., Ge W., Sun Z., Zhou X. 2021. Silica nanoparticles inhibiting the differentiation of round spermatid and chromatin remodeling of haploid period via MIWI in mice. Environ. Pollut. 284, 117446.

    Article  CAS  Google Scholar 

  20. Gong Z., Li A., Ding J., Li Q., Zhang L., Li Y., Meng Z., Chen F., Huang J., Zhou D., Hu R., Ye J., Liu W., You H. 2021. OTUD7B deubiquitinates LSD1 to govern its binding partner specificity, homeostasis, and breast cancer metastasis. Adv. Sci. (Weinh.). 8 (15), e2004504.

    Google Scholar 

  21. Shmuel-Galia L., Humphries F., Lei X., Ceglia S., Wilson R., Jiang Z., Ketelut-Carneiro N., Foley S., Pechhold S., Houghton J., Muneeruddin K., Shaffer S., McCormick B., Reboldi A., Ward D., et al. 2021. Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells. Immunity. 54, 1137‒1153. e8.

    Article  CAS  Google Scholar 

  22. Lepore A., Choy P., Lee N., Carella M., Favicchio R., Briones-Orta M., Glaser S., Alpini G., D’Santos C., Tooze R., Lorger M., Syn W., Papakyriakou A., Giamas G., Bubici C., Papa S. 2021. Phosphorylation and stabilization of PIN1 by JNK promote intrahepatic cholangiocarcinoma growth. Hepatology. 74 (5), 2561‒2579.

    Article  CAS  Google Scholar 

  23. Kapur R., Semple J. 2016. Alleviation of Gram-negative bacterial lung inflammation by targeting HECTD2. Ann. Trans. Med. 4, 488.

    Article  Google Scholar 

  24. Coon T., McKelvey A., Lear T., Rajbhandari S., Dunn S., Connelly W., Zhao J., Han S., Liu Y., Weathington N., McVerry B., Zhang Y., Chen B. 2015. The proinflammatory role of HECTD2 in innate immunity and experimental lung injury. Sci. Trans. Med. 7, 295ra109.

    Article  Google Scholar 

  25. Sun T., Wang X., He H., Sweeney C., Liu S., Brown M., Balk S., Lee G., Kantoff P. 2014. MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene. 33, 2790‒2800.

    Article  CAS  Google Scholar 

  26. Li J.H., Liu S., Zhou H., Qu L.H. Yang J.H. 2014. starBase v2.0: Decoding miRNA–ceRNA, miRNA–ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 42, D92–D97.

    Article  CAS  Google Scholar 

  27. Uhlen M., Oksvold P., Fagerberg L., Lundberg E., Jonasson K., Forsberg M., Zwahlen M., Kampf C., Wester K., Hober S., Wernerus H., Bjorling L., Ponten F. 2010. Towards a knowledge-based Human Protein Atlas. Nat. Biotechnol. 28, 1248‒1250.

    Article  CAS  Google Scholar 

  28. Uehara T., Kikuchi H., Miyazaki S., Iino I., Setoguchi T., Hiramatsu Y., Ohta M., Kamiya K., Morita Y., Tanaka H., Baba S., Hayasaka T., Setou M., Konno H. 2016. Overexpression of lysophosphatidylcholine acyltransferase 1 and concomitant lipid alterations in gastric cancer. Ann. Surg. Oncol. 23 (Suppl. 2), S206‒S213.

    Article  Google Scholar 

  29. Shida-Sakazume T., Endo-Sakamoto Y., Unozawa M., Fukumoto C., Shimada K., Kasamatsu A., Ogawara K., Yokoe H., Shiiba M., Tanzawa H., Uzawa K. 2015. Lysophosphatidylcholine acyltransferase1 overexpression promotes oral squamous cell carcinoma progression via enhanced biosynthesis of platelet-activating factor. PLoS One. 10, e0120143.

    Article  Google Scholar 

  30. Grupp K., Sanader S., Sirma H., Simon R., Koop C., Prien K., Hube-Magg C., Salomon G., Graefen M., Heinzer H., Minner S., Izbicki J., Sauter G., Schlomm T., Tsourlakis M. 2013. High lysophosphatidylcholine acyltransferase 1 expression independently predicts high risk for biochemical recurrence in prostate cancers. Mol. Oncol. 7, 1001‒1011.

    Article  CAS  Google Scholar 

  31. Liu F., Wu Y., Liu J., Ni R.J., Yang A.G., Bian K., Zhang R. 2020. A miR-205‒LPCAT1 axis contributes to proliferation and progression in multiple cancers. Biochem. Biophys. Res. Commun. 527, 474‒480.

    Article  CAS  Google Scholar 

  32. Lebok P., von Hassel A., Meiners J., Hube-Magg C., Simon R., Hoflmayer D., Hinsch A., Dum D., Fraune C., Gobel C., Moller K., Sauter G., Jacobsen F., Buscheck F., Prien K., et al. 2019. Up-regulation of lysophosphatidylcholine acyltransferase 1 (LPCAT1) is linked to poor prognosis in breast cancer. Aging. 11, 7796‒7804.

    Article  CAS  Google Scholar 

  33. Du Y., Wang Q., Zhang X., Wang X., Qin C., Sheng Z., Yin H., Jiang C., Li J., Xu T. 2017. Lysophosphatidylcholine acyltransferase 1 upregulation and concomitant phospholipid alterations in clear cell renal cell carcinoma. J. Exp. Clin. Cancer Res. 36, 66.

    Article  Google Scholar 

  34. Hu J., Ding X., Tian S., Chu Y., Liu Z., Li Y., Li X., Wang G., Wang L., Wang Z. 2021. TRIM39 deficiency inhibits tumor progression and autophagic flux in colorectal cancer via suppressing the activity of Rab7. Cell Death Dis. 12, 391.

    Article  CAS  Google Scholar 

  35. Li B., Qi Z.P., He D.L., Chen Z.H., Liu J.Y., Wong M.W., Zhang J.W., Xu E.P., Shi Q., Cai S.L., Sun D., Yao L.Q., Zhou P.H., Zhong Y.S. 2021. NLRP7 deubiquitination by USP10 promotes tumor progression and tumor-associated macrophage polarization in colorectal cancer. J. Exp. Clin. Cancer Res. 40, 126.

    Article  CAS  Google Scholar 

  36. Erokhov P.A., Kulikov A.M., Karpova Y.D., Rodoman G.V., Sumedi I.R., Goncharov A.L., Razbirin D.V., Gorelova V.S., Sharova N.P., Astakhova T.M. 2021. Proteasomes in patient rectal cancer and different intestine locations: Where does proteasome pool change? Cancers (Basel). 13, 1108.

    Article  CAS  Google Scholar 

  37. Boland K., Flanagan L., McCawley N., Pabari R., Kay E.W., McNamara D.A., Murray F., Byrne A.T., Ramtoola Z., Concannon C.G., Prehn J.H. 2016. Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer. Eur. J. Pharmacol. 780, 53‒64.

    Article  CAS  Google Scholar 

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Contributions

Lei Ma and Zhi Xu designed experiments. Lei Ma and Dehui Li carried out experiments and analyzed the results. Lei Ma wrote the manuscript, and Zhi Xu revised the manuscript. All authors approved the final manuscript.

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Correspondence to Z. Xu.

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Statement of compliance with standards of research involving humans as subjects. The experimental strategy was performed in accordance with the Declaration of Helsinki and was authorized by the ethics committee of Qingdao Municipal Hospital, Qingdao University.

All subjects agreed to participate in this study and signed a complete informed consent form.

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Ma, L., Li, D.H. & Xu, Z. HECTD2 Represses Cell Proliferation in Colorectal Cancer through Driving Ubiquitination and Degradation of LPCAT1. Mol Biol 56, 533–542 (2022). https://doi.org/10.1134/S0026893322040070

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