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Set7/9 controls proliferation and genotoxic drug resistance of NSCLC cells
Alexandra Daks1, Victoria Mamontova1, Olga Fedorova1
1Institute of Cytology, Russian Academy of Sciences, 194064, St Petersburg, Russian Federation.
Abstract:
The SET domain containing lysine-specific methyltransferase, Set7/9, covalently attaches methyl moieties to a variety of histone and non-histone substrates. Among the substrates of Set7/9 are: p53, NF-kB, PARP1, E2F1, and other transcription factors that regulate many vital processes in the cell. Through the post-translational regulation of these critical master-regulators Set7/9 is involved in regulation of cell proliferation, cancer progression, and DNA damage response. Noteworthy, the role of Set7/9 in tumorigenesis is contradictory and apparently depends on the cellular context. In this study, we investigated the effect of Set7/9 on tumorigenic characteristics of lung cancer cells. We showed that CRISPR/Cas9-mediated knock-out of Set7/9 in A549 and its shRNA-mediated knock-down in H1299 NSCLC cell lines both augment the proliferation rate of tumor cells compared to the matching wild-type cells. Mechanistically, ablation of Set7/9 increased the expression of cyclin A2 and D1 genes thereby promoting the accumulation of cells in S phase. Furthermore, knockout of Set7/9 decreased the expression of E-cadherin, whose product is critical for cell-cell interactions. Accordingly, this led to the increased migration of lung cancer cells. Finally, both ablation or pharmacological inhibition of Set7/9 enzymatic methyltransferase activity by the selective inhibitor (R)-PFI-2 sensitized NSCLC cells to genotoxic drug, doxorubicin. This effect was also recapitulated on patients-derived NSCLC cell lines. Taken together, our results suggest that Set7/9 plays anti-proliferative and DNA damage-protective roles in NSCLC cells and hence represents an attractive target for anti-cancer chemotherapy.
Insights
Set7/9, a methyltransferase, surprisingly promotes lung cancer cell proliferation and migration. Inhibiting Set7/9 sensitizes cancer cells to chemotherapy, suggesting it
Area of Science:
- Epigenetics and Cancer Biology
Background:
- The SET domain containing lysine-specific methyltransferase, Set7/9, is involved in regulating vital cellular processes through post-translational modification of transcription factors.
- Set7/9's role in tumorigenesis is context-dependent, with previous studies showing contradictory effects.
- Understanding Set7/9's specific function in lung cancer is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the precise role of Set7/9 in the tumorigenic characteristics of non-small cell lung cancer (NSCLC) cells.
- To explore the potential of Set7/9 as a therapeutic target in lung cancer treatment.
Main Methods:
- Utilized CRISPR/Cas9 gene editing for Set7/9 knockout in A549 NSCLC cells.
- Employed shRNA for Set7/9 knockdown in H1299 NSCLC cells.
- Assessed cell proliferation, cell cycle progression, gene expression (cyclin A2, D1, E-cadherin), cell migration, and sensitivity to doxorubicin following Set7/9 manipulation or inhibition with (R)-PFI-2.
Main Results:
- Ablation of Set7/9 significantly increased proliferation and promoted S-phase accumulation by upregulating cyclin A2 and D1.
- Set7/9 deficiency led to decreased E-cadherin expression, enhancing cell migration.
- Both Set7/9 knockout/knockdown and pharmacological inhibition with (R)-PFI-2 sensitized NSCLC cells to doxorubicin, an effect observed in patient-derived cells.
Conclusions:
- Set7/9 exhibits anti-proliferative and DNA damage-protective functions in NSCLC cells, contrary to some previous assumptions.
- Targeting Set7/9 enzymatic activity represents a promising therapeutic strategy for enhancing chemotherapy efficacy in lung cancer.
- Set7/9 is a potential anti-cancer target for NSCLC treatment.
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