# Mechanisms of BAP1 activity in human cancer development

> **NIH NIH R01** · UNIVERSITY OF HAWAII AT MANOA · 2021 · $423,075

## Abstract

PROJECT SUMMARY
This application investigates mechanisms of gene and environment interaction in carcinogenesis.
Malignant mesothelioma (MM) is frequent in individuals continuously exposed to carcinogenic mineral
fibers such as asbestos and erionite, but it is very rare in those with limited or no exposure. Genetics
influences susceptibility to MM. We have recently demonstrated that carriers of germline BAP1 mutations
have increased incidence of multiple cancer types, including MM (we named this condition the “BAP1
cancer syndrome”). In some BAP1-mutation carrying families, MM accounts for more than 50% of
deaths, and we found that this may be due to increased susceptibility to MM from exposure to modest
amounts of asbestos that would normally not cause MM in the general population. We also found that
heterozygous BAP1 germline mutations in addition to asbestos, also increase susceptibility to malignant
transformation following exposure to Ionizing Irradiation and ultraviolet (UV) light –which may account for
the high prevalence of melanomas and skin carcinomas in carriers of BAP1 mutations. BAP1 is the first and
so far the only gene shown to regulate environmental carcinogenesis. The mechanism(s) by which
mutated BAP1 causes MM pathogenesis are being elucidated. Inositol 1,4,5-trisphosphate (IP3) binds and
activates the IP3 receptors (IP3Rs). We demonstrated that BAP1 is present in the endoplasmic reticulum
(ER) where it regulates the activity of the IP3-Receptor-3 (IP3R3), the main ER channel that controls Ca2+
release from the ER to the cytoplasm to the mitochondria, regulating apoptosis. We discovered that reduced
levels of BAP1 in carriers of heterozygous BAP1 mutations impair apoptosis and favor cellular transformation
of cells that accumulated DNA damage following exposure to asbestos, IR and UV-light. We also discovered
that “normal” primary cells of carriers of heterozygous germline BAP1 mutations derive energy from aerobic
glycolysis, known as Warburg effect, which so far had been considered a hallmark of cancer cells. We
identified a specific metabolic signature associated with the Warburg effect by studying the metabolites present
in the plasma of carriers of heterozygous germline BAP1 mutations. Our central hypothesis is that changes in
Ca2+ concentration lead to increased resistance of cells containing BAP1 mutations to apoptosis and to
changes in metabolic pathways that in turn are responsible for the very high cancer penetrance observed in
BAP1 mutation carriers. To address this hypothesis we will examine the following specific Aims:
AIM 1: To study the mechanisms by which BAP1 mutations induce a “Warburg effect”.
AIM 2: To study the hypothesis that the Warburg effect is HIF-1α-independent in BAP1+/- cells.
AIM 3: To study the contributions of calcium signaling and metabolic alterations due to germline BAP1
mutations to MM development.
To elucidate the activity of BAP1 on the I P 3 R 3 and the related effects on cancer penetrance, ...

## Key facts

- **NIH application ID:** 10071143
- **Project number:** 5R01CA237235-02
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** MICHELE CARBONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,075
- **Award type:** 5
- **Project period:** 2019-12-13 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071143

## Citation

> US National Institutes of Health, RePORTER application 10071143, Mechanisms of BAP1 activity in human cancer development (5R01CA237235-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10071143. Licensed CC0.

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