Singapore's research community has achieved a significant milestone in the fight against some of the most challenging cancers, thanks to a groundbreaking study from scientists at the National Cancer Centre Singapore (NCCS) and Duke-NUS Medical School. This collaboration has illuminated the intricate mechanisms of the BAP1 tumour suppressor protein, offering fresh insights into why certain aggressive cancers progress rapidly and paving the way for targeted therapies.
The research, detailed in a paper published on April 1, 2026, in Science Translational Medicine, reveals how BAP1 functions as a 'cellular quality control supervisor' by removing ubiquitin tags from proteins involved in DNA repair. When BAP1 is mutated or lost, this process falters, leading to genomic instability and uncontrolled cell growth in cancers such as mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal cell carcinoma.
Understanding BAP1: The Tumour Suppressor's Critical Role
BRCA1-associated protein 1 (BAP1), first identified in 1998, is a deubiquitinating enzyme (DUB) primarily located in the nucleus. Ubiquitination is a post-translational modification where ubiquitin molecules are attached to proteins, marking them for degradation or altering their function. BAP1 reverses this by cleaving ubiquitin, thereby stabilizing key proteins essential for cellular homeostasis.
In healthy cells, BAP1 regulates the cell cycle, DNA damage repair, and apoptosis (programmed cell death). Its loss disrupts these processes, allowing damaged cells to proliferate. Mutations in BAP1 are found in up to 85% of uveal melanomas, 60% of mesotheliomas, and significant portions of cholangiocarcinomas and renal cell carcinomas, making it a hallmark of aggressive disease.
This study marks the first comprehensive mapping of BAP1's deubiquitination targets across multiple cancer types, using advanced proteomics like K-ε-GG ubiquitin remnant motif pulldown and mass spectrometry. The findings pinpoint BAP1's direct interaction with global genome nucleotide excision repair (GG-NER) pathway proteins: damage-specific DNA binding protein 1 (DDB1), UV excision repair protein RAD23 homolog B (RAD23B), and COP9 signalosome complex subunit 7B (COPS7B).
The Pancancer Approach: From Cell Lines to Animal Models
Led by Dr. Hong Jing Han, Principal Research Scientist at Duke-NUS' Cancer & Stem Cell Biology Programme, and Professor Teh Bin Tean, Deputy CEO (Venture & Enterprise) at NCCS, the team employed a multi-model strategy. They analyzed patient-derived cell lines, organoids, and xenograft mouse models from BAP1-mutated mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal cell carcinoma.
Techniques such as chromatin immunoprecipitation (ChIP) sequencing, assay for transposase-accessible chromatin (ATAC) sequencing, and transcriptomics revealed BAP1's chromatin colocalization with lysine-specific demethylase 1 (LSD1) and poly(ADP-ribose) polymerase 1 (PARP1). These interactions facilitate nucleotide excision repair (NER), where LSD1 relaxes chromatin structure for DNA access, and PARP1 aids lesion recognition.
The rigorous pancancer validation ensures the findings' broad applicability, addressing a gap in prior BAP1 research focused on single cancer types.
Targeting Aggressive Cancers: Mesothelioma, Uveal Melanoma, and Beyond
Mesothelioma, often linked to asbestos exposure, has a dismal five-year survival rate below 10%. Uveal melanoma, the most common primary intraocular malignancy, metastasizes to the liver in 50% of cases. Cholangiocarcinoma, or bile duct cancer, and clear cell renal cell carcinoma also evade standard therapies like chemotherapy and immunotherapy.
In Singapore, while overall cancer incidence is rising with an aging population, these BAP1-associated cancers represent a growing challenge. For instance, renal cell carcinoma accounts for about 3% of cancers, with BAP1 mutations exacerbating outcomes. The study highlights how BAP1 loss drives shared vulnerabilities across these 'pancancers,' enabling unified therapeutic strategies.
By stabilizing NER proteins, BAP1 prevents UV-induced and bulky lesion damage accumulation. Its deficiency causes synthetic lethality—cell death triggered by inhibiting compensatory pathways.
Synthetic Lethality: LSD1 and PARP1 Inhibitors as Game-Changers
High-throughput screening of 422 anti-cancer agents identified SP2509, an LSD1 inhibitor, as selectively toxic to BAP1-deficient cells while sparing healthy ones. Olaparib, a PARP1 inhibitor already approved for BRCA-mutated cancers, also showed efficacy.
Remarkably, combining SP2509 with Olaparib induced synergy: enhanced apoptosis, reduced migration/invasion, and halted tumor growth in preclinical models. In mouse xenografts, the combo extended survival significantly, with tumors shrinking up to 70%. For details on the study, see the full publication here.
LSD1 (KDM1A) demethylates histones to open chromatin for repair, while PARP1 poly-ADP-ribosylates proteins for damage signaling. Dual inhibition overwhelms BAP1-loss cells, trapping them in irreparable DNA damage.
Preclinical Validation and Biomarker Potential
Patient-derived organoids mirrored clinical responses, confirming translatability. BAP1 levels and downstream pathway activity emerged as biomarkers for stratifying patients, predicting therapy response, and monitoring progress.
"Understanding how BAP1 works at the molecular level creates new opportunities to test drug combinations that target vulnerabilities in DNA repair," said Dr. Hong Jing Han.
Professor Teh added, "The synergistic activity... represents a shift from single-drug treatments to more effective, mechanism-based combination strategies."
Singapore's Academic Medicine Ecosystem in Action
This breakthrough exemplifies Singapore's integrated academic medicine model via the SingHealth Duke-NUS partnership. Duke-NUS, established in 2005 as a collaboration between Duke University and the National University of Singapore, trains clinician-scientists and drives translational research.
NCCS, Asia's first comprehensive cancer centre, integrates care, research, and education. Funded by Singapore's Ministry of Health (NMRC) and others, such synergies accelerate discoveries from bench to bedside. Read more on the SingHealth announcement.
Future Directions: Clinical Trials and Global Impact
The team plans trials for LSD1/PARP1 combos in BAP1-mutated patients. SP2509 is in early trials for other cancers, while Olaparib's profile supports rapid advancement. Challenges include patient selection via biomarkers and overcoming resistance.
In Singapore, where cancer is the top killer, this could personalize care, reducing reliance on one-size-fits-all approaches. Globally, with millions affected annually, it promises hope for underserved cancers.
Broader Implications for Cancer Research and Higher Education
Duke-NUS' role underscores Singapore's rise as a biotech hub, attracting talent and funding. For aspiring researchers, programs like Duke-NUS PhD pathways offer hands-on translational experience.
The study advances precision oncology, emphasizing multi-omics integration and synthetic lethality—a strategy pioneered in BRCA cancers now extended to BAP1.
Stakeholder Perspectives and Patient Hope
Oncologists view this as a paradigm shift for BAP1 cancers, historically resistant. Patients gain optimism from mechanism-based therapies minimizing side effects.
Singapore's ecosystem ensures swift translation, with SingHealth's clinical infrastructure ready for trials.