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Disruption of the MSL complex inhibits tumour maintenance by exacerbating chromosomal instability
Josep Monserrat1, Cristina Morales Torres1, Louise Richardson1
1Cancer Epigenetics Laboratory, Francis Crick Institute, London, UK.
Abstract:
Rewiring of cellular programmes in malignant cells generates cancer-specific vulnerabilities. Here, using an unbiased screening strategy aimed at identifying non-essential genes required by tumour cells to sustain unlimited proliferative capacity, we identify the male-specific lethal (MSL) acetyltransferase complex as a vulnerability of genetically unstable cancers. We find that disruption of the MSL complex and consequent loss of the associated H4K16ac mark do not substantially alter transcriptional programmes but compromise chromosome integrity and promote chromosomal instability (CIN) that progressively exhausts the proliferative potential of cancer cells through a p53-independent mechanism. This effect is dependent on pre-existing genomic instability, and normal cells are insensitive to MSL disruption. Using cell- and patient-derived xenografts from multiple cancer types, we show that excessive CIN induced by MSL disruption inhibits tumour maintenance. Our findings suggest that targeting MSL may be a valuable means to increase CIN beyond the level tolerated by cancer cells without inducing severe adverse effects in normal tissues.
Insights
Targeting the male-specific lethal (MSL) complex exploits cancer
Area of Science:
- Cancer Biology
- Epigenetics
- Genomics
Background:
- Malignant cells rewire cellular programs, creating vulnerabilities.
- Identifying non-essential genes crucial for cancer proliferation is key.
Purpose of the Study:
- To identify non-essential genes critical for cancer cell unlimited proliferation.
- To investigate the role of the male-specific lethal (MSL) complex in cancer.
Main Methods:
- Unbiased screening for non-essential genes in tumor cells.
- Disruption of the MSL complex and assessment of H4K16ac mark.
- Analysis of chromosome integrity and chromosomal instability (CIN).
- Evaluation in cell- and patient-derived xenografts across multiple cancer types.
Main Results:
- MSL complex disruption compromises chromosome integrity and promotes CIN.
- CIN induced by MSL disruption exhausts cancer cell proliferation via a p53-independent pathway.
- This effect is dependent on pre-existing genomic instability; normal cells are unaffected.
- Excessive CIN inhibits tumor maintenance in preclinical models.
Conclusions:
- The MSL complex is a vulnerability in genetically unstable cancers.
- Targeting MSL can induce excessive, cancer-specific CIN, inhibiting tumor growth.
- This strategy offers a potential therapeutic approach with limited toxicity to normal tissues.
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