Skip to main content
SpringerLink
Log in

TMEM120A-mediated regulation of chemotherapy sensitivity in colorectal cancer cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Enhancing chemotherapy sensitivity in colorectal cancer (CRC) is critical for improving treatment outcomes. TMEM120A has been reported to interact with coenzyme A (CoA), but its biological significance in CRC is unknown. In this study, we aimed to investigate the functional implications of TMEM120A in CRC and its impact on chemotherapy sensitivity.

Methods

Stable knockout of TMEM120A in CRC cell lines was conducted using CRISPR/Cas9 technology. Overexpression of various derivatives of TMEM120A was achieved through lentiviral transduction. Cell fractionation was employed to isolate the nuclear and cytoplasmic fraction. Total histones were isolated by acid extraction and then subjected to determine histone acetylation levels using western blot analysis. Cell viability was evaluated using the MTS assay.

Results

We demonstrate that TMEM120A’s nuclear localization is crucial for its role in regulating CRC chemosensitivity. Mechanistically, the nuclear subpopulation of TMEM120A plays a key role in sustaining the nuclear CoA levels, which in turn influences the levels of nuclear acetyl-CoA and histone acetylation in CRC cells. Notably, direct inhibition of histone acetylation recapitulated the phenotypic effects observed upon TMEM120A depletion, leading to increased chemosensitivity in CRC cells.

Conclusion

Our study provides novel insights into the role of TMEM120A in modulating chemotherapy sensitivity in CRC. Nuclear TMEM120A regulates CoA levels, which in turn modulates nuclear acetyl-CoA levels and histone acetylation, thereby influencing the response of CRC cells to chemotherapy agents. Targeting TMEM120A-mediated pathways may represent a promising strategy for enhancing chemotherapy efficacy in CRC treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

Data generated or analyzed during this study are available from the corresponding author upon reasonable request.

References

  1. Hossain MS et al (2022) Colorectal cancer: a review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers 14:1732. https://doi.org/10.3390/cancers14071732

    Article  PubMed  PubMed Central  Google Scholar 

  2. Biller LH, Schrag D (2021) Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA 325:669–685. https://doi.org/10.1001/jama.2021.0106

    Article  CAS  PubMed  Google Scholar 

  3. McQuade RM, Stojanovska V, Bornstein JC, Nurgali K (2017) Colorectal cancer chemotherapy: the evolution of treatment and new approaches. Curr Med Chem 24:1537–1557. https://doi.org/10.2174/0929867324666170111152436

    Article  CAS  PubMed  Google Scholar 

  4. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B (2017) The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull 7:339–348. https://doi.org/10.15171/apb.2017.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alfarouk KO et al (2015) Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int 15:71. https://doi.org/10.1186/s12935-015-0221-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bradshaw PC (2021) Acetyl-CoA metabolism and histone acetylation in the regulation of aging and lifespan. Antioxidants (Basel, Switzerland) 10:572. https://doi.org/10.3390/antiox10040572

    Article  CAS  PubMed  Google Scholar 

  7. Yi CH, Vakifahmetoglu-Norberg H, Yuan J (2011) Integration of apoptosis and metabolism. Cold Spring Harb Symp Quant Biol 76:375–387. https://doi.org/10.1101/sqb.2011.76.010777

    Article  CAS  PubMed  Google Scholar 

  8. Martínez-Reyes I, Chandel NS (2018) Acetyl-CoA-directed gene transcription in cancer cells. Genes Dev 32:463–465. https://doi.org/10.1101/gad.315168.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Feron O (2019) The many metabolic sources of acetyl-CoA to support histone acetylation and influence cancer progression. Ann Transl Med 7:S277. https://doi.org/10.21037/atm.2019.11.140

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sebastián C, Mostoslavsky R (2017) The various metabolic sources of histone acetylation. Trends Endocrinol Metab 28:85–87. https://doi.org/10.1016/j.tem.2016.11.001

    Article  CAS  PubMed  Google Scholar 

  11. Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A (2020) Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol 17:111–130. https://doi.org/10.1038/s41575-019-0230-y

    Article  PubMed  PubMed Central  Google Scholar 

  12. Qin J, Wen B, Liang Y, Yu W, Li H (2020) Histone modifications and their role in colorectal cancer (review). Pathol Oncol Res POR 26:2023–2033. https://doi.org/10.1007/s12253-019-00663-8

    Article  PubMed  Google Scholar 

  13. Nenkov M, Ma Y, Gaßler N, Chen Y (2021) Metabolic reprogramming of colorectal cancer cells and the microenvironment: implication for therapy. Int J Mol Sci 22:6262. https://doi.org/10.3390/ijms22126262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Beaulieu-Laroche L et al (2020) TACAN is an ion channel involved in sensing mechanical pain. Cell 180:956-967.e917. https://doi.org/10.1016/j.cell.2020.01.033

    Article  CAS  PubMed  Google Scholar 

  15. Batrakou DG, de Las Heras JI, Czapiewski R, Mouras R, Schirmer EC (2015) TMEM120A and B: nuclear envelope transmembrane proteins important for adipocyte differentiation. PLoS One 10:e0127712. https://doi.org/10.1371/journal.pone.0127712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li S et al (2022) Gain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation. Nat Commun 13:105. https://doi.org/10.1038/s41467-021-27670-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rong Y et al (2021) TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells. Elife 10:e71474. https://doi.org/10.7554/eLife.71474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xue J et al (2021) TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase. Elife 10:e71220. https://doi.org/10.7554/eLife.71220

    Article  PubMed  PubMed Central  Google Scholar 

  19. Guertin DA, Wellen KE (2023) Acetyl-CoA metabolism in cancer. Nat Rev Cancer 23:156–172. https://doi.org/10.1038/s41568-022-00543-5

    Article  CAS  PubMed  Google Scholar 

  20. St Paul M et al (2021) Coenzyme A fuels T cell anti-tumor immunity. Cell Metab 33:2415-2427.e2416. https://doi.org/10.1016/j.cmet.2021.11.010

    Article  CAS  PubMed  Google Scholar 

  21. He W, Li Q, Li X (2023) Acetyl-CoA regulates lipid metabolism and histone acetylation modification in cancer. Biochim Biophys Acta Rev Cancer 1878:188837. https://doi.org/10.1016/j.bbcan.2022.188837

    Article  CAS  PubMed  Google Scholar 

  22. Ran FA et al (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308. https://doi.org/10.1038/nprot.2013.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shechter D, Dormann HL, Allis CD, Hake SB (2007) Extraction, purification and analysis of histones. Nat Protoc 2:1445–1457. https://doi.org/10.1038/nprot.2007.202

    Article  CAS  PubMed  Google Scholar 

  24. Gout I (2018) Coenzyme A, protein CoAlation and redox regulation in mammalian cells. Biochem Soc Trans 46:721–728. https://doi.org/10.1042/bst20170506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G (2015) Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab 21:805–821. https://doi.org/10.1016/j.cmet.2015.05.014

    Article  CAS  PubMed  Google Scholar 

  26. Srinivasan B, Sibon OC (2014) Coenzyme A, more than ‘just’ a metabolic cofactor. Biochem Soc Trans 42:1075–1079. https://doi.org/10.1042/bst20140125

    Article  CAS  PubMed  Google Scholar 

  27. Zhang B, Chen D, Liu B, Dekker FJ, Quax WJ (2020) A novel histone acetyltransferase inhibitor A485 improves sensitivity of non-small-cell lung carcinoma cells to TRAIL. Biochem Pharmacol 175:113914. https://doi.org/10.1016/j.bcp.2020.113914

    Article  CAS  PubMed  Google Scholar 

  28. Lasko LM et al (2017) Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature 550:128–132. https://doi.org/10.1038/nature24028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang N, Ma T, Yu B (2023) Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduct Target Ther 8:69. https://doi.org/10.1038/s41392-023-01341-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu D, Qiu Y, Jiao Y, Qiu Z, Liu D (2020) Small molecules targeting HATs, HDACs, and BRDs in cancer therapy. Front Oncol 10:560487. https://doi.org/10.3389/fonc.2020.560487

    Article  PubMed  PubMed Central  Google Scholar 

  31. Peserico A, Simone C (2011) Physical and functional HAT/HDAC interplay regulates protein acetylation balance. J Biomed Biotechnol 2011:371832. https://doi.org/10.1155/2011/371832

    Article  CAS  PubMed  Google Scholar 

  32. Bishop TR et al (2023) Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition. Nat Chem Biol. https://doi.org/10.1038/s41589-023-01320-7

    Article  PubMed  Google Scholar 

  33. Hogg SJ et al (2021) Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition. Mol Cell 81:2183-2200.e2113. https://doi.org/10.1016/j.molcel.2021.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee JH, Choy ML, Marks PA (2012) Mechanisms of resistance to histone deacetylase inhibitors. Adv Cancer Res 116:39–86. https://doi.org/10.1016/b978-0-12-394387-3.00002-1

    Article  CAS  PubMed  Google Scholar 

  35. Robey RW et al (2011) Histone deacetylase inhibitors: emerging mechanisms of resistance. Mol Pharm 8:2021–2031. https://doi.org/10.1021/mp200329f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

We would like to clarify that this research project was conducted without any external funding or financial support. The study was carried out as part of our academic research efforts and was not supported by any specific grants or funding sources.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Yantaishan Hospital, Yantai, Shandong, China

    Li Wang

  2. Department of Gastroenterology, Qixia City People’s Hospital, Qixia, Shandong, China

    Xiaoxia Liu

Authors
  1. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoxia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: LW and XL; Resources: XL; Data curation: XL; Formal analysis: LW and XL; Supervision: XL; Validation: LW and XL; Investigation: LW and XL; Visualization: XL; Methodology: LW and XL; Project administration: XL; Writing—original draft: LW; Writing—review and editing: LW and XL.

Corresponding author

Correspondence to Xiaoxia Liu.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Liu, X. TMEM120A-mediated regulation of chemotherapy sensitivity in colorectal cancer cells. Cancer Chemother Pharmacol 93, 11–22 (2024). https://doi.org/10.1007/s00280-023-04594-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-023-04594-9

Keywords

Search

Navigation