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Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents
Constanze Schneider1,2, Gabriela Alexe1,2, Lucy A Merickel1
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Abstract:
Cancer-directed drugs are often clinically deployed without definitive understanding of their molecular mechanisms of action (MOA). Hypomethylating agents (HMAs), which result in the degradation of the DNA methyltransferase 1 (DNMT1), have been deployed for decades in the treatment of haematological malignancies1,2. The precise mechanism of action of these drugs, however, has been debated, rendering the design of rational combination therapies challenging. Here, we identified the deubiquitinating enzyme USP48 as a crucial regulator of posttranslational histone modification in the context of DNA demethylation. USP48 loss selectively enhances response to DNMT1 inhibition, leading to a rapid induction of cell death. We demonstrate that USP48 is localized at sites of DNA damage and deubiquitinates H2A variants and proteins important for DNA damage repair. Functionally, loss of USP48 triggers an increase in chromatin accessibility upon HMA treatment, rendering AML cells more susceptible to DNA damage. Our results support USP48 as a posttranslational histone modifier for chromatin stability and DNA damage in response to HMA-related DNA demethylation. These findings propose USP48 as a new target for combination therapy with HMAs for acute myeloid leukaemia (AML).
Insights
Scientists discovered that inhibiting USP48 enhances cancer drug effectiveness. Loss of USP48 boosts responses to hypomethylating agents, causing cancer cell death and offering new combination therapy targets for acute myeloid leukaemia.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Hypomethylating agents (HMAs) are used for haematological malignancies but their precise molecular mechanisms of action (MOA) remain debated.
- Understanding MOA is crucial for designing effective combination therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms of hypomethylating agents (HMAs) in cancer treatment.
- To identify novel targets for combination therapies in acute myeloid leukaemia (AML).
Main Methods:
- Investigated the role of deubiquitinating enzyme USP48 in DNA demethylation and histone modification.
- Assessed the effect of USP48 loss on cellular response to DNMT1 inhibition.
- Analyzed USP48 localization at DNA damage sites and its function in deubiquitinating histone variants.
Main Results:
- USP48 was identified as a key regulator of posttranslational histone modification during DNA demethylation.
- Loss of USP48 selectively enhanced cellular sensitivity to DNMT1 inhibition, inducing rapid cell death.
- USP48 deubiquitinates H2A variants and DNA damage repair proteins, increasing chromatin accessibility upon HMA treatment.
Conclusions:
- USP48 acts as a posttranslational histone modifier impacting chromatin stability and DNA damage response.
- Targeting USP48 in combination with HMAs presents a promising therapeutic strategy for acute myeloid leukaemia (AML).
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