# Role of hypoxia in altering hnRNP A2B1-mediated interaction with m6A to promote breast cancer progression

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2020 · $33,959

## Abstract

Project Summary / Abstract
Background: N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of eukaryotic
mRNA and plays an important role in mediating gene expression through regulation of alternative splicing and
RNA turnover. Recent studies have implicated dysregulation of m6A residues in breast cancer initiation and
progression, specifically noting that hypoxic stress causes a significant reduction of m6A levels that is correlated
with an overall increase in metastatic phenotypes. Hypoxia has also been linked to aberrant alternative splicing
in breast cancer, though how this relationship is mediated remains to be elucidated. Notably, the RNA binding
ability of the pre-mRNA processing protein hnRNP A2/B1 is influenced by m6A residues, and this protein has
also been implicated in the invasion and migration of breast cancer cells. Both A2/B1 and m6A are involved in
the regulation of alternative splicing, and our preliminary data suggests that m6A modifications directly inhibit
A2/B1 binding. Therefore, reduced m6A levels during hypoxia may cause a significant increase in A2/B1 activity.
Objective / Hypothesis: This proposal hypothesizes that depletion of m6A residues due to hypoxic stress
causes an increase in hnRNP A2/B1 binding of cancer-associated genes leading to dysregulated RNA splicing
and subsequent breast cancer progression. This idea will be investigated by characterizing the relationship
between A2/B1 activity and m6A levels in hypoxic breast cancer cells and determining whether differential m6A
deposition can influence A2/B1-mediated alternative splicing and promote breast cancer phenotypes.
Specific Aims: To examine how hypoxia influences m6A:A2/B1-mediated RNA splicing in breast cancer,
hypoxia-induced m6A:A2/B1-dependent isoforms will be identified and expressed in normoxic cancer cells to
evaluate whether they can mediate a cancer phenotype. To characterize the molecular mechanism of how m6A
residues alter A2/B1 binding during hypoxia, a modified CLIP strategy will be used to identify m6A-depedent
A2/B1 binding sites that will then be modified to confirm the residues are directly modulating A2/B1 binding.
Training Plan / Environment: To achieve my goal of becoming an independent cancer investigator, I have
developed a training plan composed of three specific objectives: 1) to learn new molecular/cancer biology and
computational approaches, 2) to improve my scientific writing and oral communication skills, and 3) to develop
a professional network of colleagues and mentors. The training environment fostered at the University of
Colorado AMC is uniquely equipped to help me achieve these goals through maintaining state-of-the-art facilities
and funding initiatives that are directly aligned with my interest in RNA and cancer research.
Health Relevance: The NCI recently characterized RNA biology as one of the most influential areas in molecular
medicine. By investigating how hypoxia influences m6A-mediated h...

## Key facts

- **NIH application ID:** 10066048
- **Project number:** 1F31CA247343-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Justin T Roberts
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,959
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066048

## Citation

> US National Institutes of Health, RePORTER application 10066048, Role of hypoxia in altering hnRNP A2B1-mediated interaction with m6A to promote breast cancer progression (1F31CA247343-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066048. Licensed CC0.

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