# An antisense RNA-mediated regulatory program that drives cancer metastasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $417,339

## Abstract

PROJECT SUMMARY
 Post-transcriptional regulatory programs play a major role in shaping the aberrant gene expression landscape
that is a hallmark of cancer progression. We have recently demonstrated that specific classes of non-coding
RNAs, such as tRNAs (Goodarzi et al, Cell, 2016) and tRNA fragments (Goodarzi et al, Cell, 2015), play major
roles in breast cancer metastasis as post-transcriptional regulators of gene expression. However, these
regulatory RNAs are but a fraction of non-coding RNAs that are differentially expressed in highly metastatic cells.
For example, antisense RNAs are a large but often ignored class of non-coding RNAs with poorly understood
functions in the cell. We recently performed a systematic analysis of antisense RNAs expressed in a panel of
poorly and highly metastatic breast cancer cells. We observed tens of antisense RNAs that are associated with
metastatic capacity. Antisense RNAs can function as post-transcriptional regulators through their ability to form
stable duplexes with their sense counterparts. However, the underlying molecular mechanisms and their role in
gene expression regulation remains largely unknown. Here, we propose a detailed dissection of our top
candidate antisense RNA, which targets the 3' UTR of the gene NQO1 and is hence named NQO1-AS, and its
function in promoting breast cancer metastasis. We hypothesize that NQO1-AS forms a stable duplex with the
3' UTR of NQO1 which precludes the protein HNRNPC from binding. HNRNPC likely acts as a regulator of
alternative poly(A) site selection in NQO1 mRNA, shifting the equilibrium towards an isoform with a truncated 3'
UTR. We hypothesize that this truncated transcript isoform has a shorter life-span. Thus, by over-expressing
NQO1-AS, highly metastatic cells post-transcriptionally increase the expression of NQO1. Enhanced NQO1
activity enables cancer cells to withstand the oxidative stress experienced during metastasis. In this study, we
seek to perform a detailed dissection of this pathway, understand its role in metastasis, and test its clinical
relevance in patients. Importantly, the enhanced NQO1 activity in highly metastatic cells can be exploited, using
adjuvant therapies, to specifically target metastatic cells in patients with invasive breast cancer.

## Key facts

- **NIH application ID:** 10652579
- **Project number:** 5R01CA240984-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Hani Goodarzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $417,339
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652579

## Citation

> US National Institutes of Health, RePORTER application 10652579, An antisense RNA-mediated regulatory program that drives cancer metastasis (5R01CA240984-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10652579. Licensed CC0.

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