# NIH grant: The impact of obesity on mutagenesis at H-DNA sequences and prostate cancer progression (1R01CA314250-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01CA314250-01)

## retained text



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NIH grant 1R01CA314250-01: The impact of obesity on mutagenesis at H-DNA sequences and prostate cancer progression
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: John  DiGiovanni. Award: $626203.
Start: 2026-07-16T00:00:00.
PROJECT SUMMARY
Obesity is an important risk factor for many cancer types in both men and women. In men, obesity contributes
to more aggressive prostate cancer (PCa) and higher mortality rates. We have found that sequences with the
capacity to adopt alternative (i.e. non-B) DNA structures, e.g., H-DNA, are significantly enriched at mutation
“hotspots” in human cancer genomes, implicating them in cancer development and progression. However, the
mechanisms linking obesity to cancer and the generation of mutation hotspots are not known. With the increase
in global obesity rates, there is a critical need to fill these gaps in knowledge. The long-term goal is to elucidate
the mechanisms of obesity-associated DNA structure-induced genetic instability in PCa to aid the development
of novel strategies to prevent and/or treat it. Toward this goal, we found that human non-B DNA is mutagenic
and can stimulate the formation of DNA double-strand breaks (DSBs) in novel mutation-reporter mice, and that
obesity substantially increases mutagenesis and DSBs at these sequences in various tissues, including prostate
tissue. Mechanistically, we found that flap endonuclease 1 (FEN1) is involved in processing H-DNA, and its
protein levels and phosphorylation at S187 are increased in prostate tissue from obese mice compared to normal
weight mice. We also found a decreased association of FEN1 with PCNA, suggesting that obesity alters protein-
protein interactions and the function of FEN1 via altered posttranslational modifications, potentially altering its
ability to process mutagenic H-DNA. Additionally, we found that H-DNA is more susceptible to oxidative DNA
damage than B-DNA, with increased 8-oxo-dG and gH2AX levels in prostate tissue from obese mice. The
immediate objectives of this proposal are to elucidate the mechanisms of obesity-associated DNA structure-
induced genetic instability in mouse and human prostate tissue and tumors and determine its potential role in
obesity-driven PCa progression. Thus, the proposed studies will address an important gap in knowledge to
determine mechanisms of obesity-driven PCa progression and specifically the role of obesity-induced genetic
instability at endogenous H-DNA sequences. We will test the novel hypothesis that obesity increases DNA
structure-induced genetic instability in prostate tissue and tumors due to increased DNA damage at and/or
altered processing of these endogenous mutation hotspots, contributing to PCa aggressiveness in the following
specific aims: 1: measure the impact of obesity on DNA structure-induced mutagenesis in prostate tissue and
tumors; 2: determine the impact of obesity on DNA damage and repair at endogenous mutation hotspots in vivo;
and 3: examine the impact of altered phosphorylation of FEN1 at S187 on the mutagenicity of H-DNA and PCa
progression in vivo. The expected contribution is a better understanding of how obesity influences genetic
instability at endogenous mutation hotspots in prostate cancer. This is expected to have a significant impact
because the results will help to identify novel mechanisms and targets that can be modulated for the prevention
and/or treatment of obesity-driven PCa progression to reduce prostate cancer specific mortality.
Obesity is an important risk factor for many cancer types and in men, obesity contributes to more aggressive
prostate cancer (PCa) and higher mortality rates. We have found that sequences with the capacity to adopt
alternative (i.e. non-B) DNA structures, e.g., H-DNA, are significantly enriched at mutation “hotspots” in human
cancer genomes, implicating them in cancer development and progression. However, the mechanisms linking
obesity to cancer and the generation of mutation hotspots are not known. With the increase in global obesity
rates, there is a critical need to fill these gaps in knowledge. The long-term goal is to elucidate the mechanisms
of obesity-associated DNA structure-induced genetic instability in PCa to aid the development of novel
strategies to prevent and/or treat it. Toward this goal, we found that human non-B DNA is mutagenic and can
stimulate the formation of DNA double-strand breaks (DSBs) in mice, and that obesity increases mutagenesis
and DSBs at these sequences in prostate tissue. We found that flap endonuclease 1 (FEN1) is involved in
processing H-DNA, and its protein levels and phosphorylation at S187 are increased in prostate tissue from
obese mice compared to normal weight mice. We also found a decreased association of FEN1 with PCNA,
suggesting that obesity alters protein-protein interactions and the function of FEN1 via altered posttranslational
modifications, potentially altering its ability to process mutagenic H-DNA. We also found that H-DNA is more
susceptible to oxidative DNA damage than B-DNA, with increased damage in prostate tissue from obese mice.
The immediate objectives are to elucidate the mechanisms of obesity-associated DNA structure-induced
genetic instability in mouse and human prostate tumors and determine its potential role in obesity-driven PCa
progression. Thus, the proposed studies will address an important gap in knowledge. The HiMyc mouse model
to be used in the proposed research is an excellent model for studying the impact of obesity on PCa
progression as it provides a physiologically relevant prostate tumor model that will generate mechanistic data
translatable to human PCa. We will test the novel hypothesis that obesity increases DNA structure-induced
genetic instability in prostate tissue and tumors due to increased DNA damage at and/or altered processing of
these endogenous mutation hotspots, contributing to PCa aggressiveness in the following aims: 1: measure
the impact of obesity on DNA structure-induced mutagenesis in prostate tissue and tumors; 2: determine the
impact of obesity on DNA damage and repair at mutation hotspots in vivo; and 3: examine the impact of altered
phosphorylation of FEN1 at S187 on the mutagenicity of H-DNA and PCa progression in vivo. The expected
contribution is a greater understanding of how obesity influences genetic instability at mutation hotspots in
PCa. This should have a significant impact because the results will help to identify novel mechanisms and
targets for the prevention and/or treatment of obesity-driven PCa progression to reduce PCa specific mortality.
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