Abstract 3038: Delineating the role of Arid3B in normal and malignant differentiation of esophageal and cervical stratified squamous epithelia

Antisense RNAs are ubiquitous in human cells, yet the role that they play in healthy and diseased states remains largely unexplored. Here, we developed a computational framework to catalog and profile antisense RNAs and applied it to poorly and highly metastatic breast cancer cell lines. We identified one antisense RNA that plays a functional role in driving breast cancer progression by upregulating the redox enzyme NQO1, and hence named NQO1-antisense RNA or NQO1-AS. This upregulation occurs via a stabilizing interaction between NQO1-AS and its complementary region in the 3'UTR of NQO1 mRNA. By increasing expression of NQO1 protein, breast cancer cells are able to tolerate higher levels of oxidative stress, enabling them to colonize the lung. During this process the cancer cells become dependent on NQO1 to protect them from ferroptosis. We have shown that this dependence can be exploited therapeutically in xenograft models of metastasis. Together, our findings establish a previously unknown role for NQO1-AS in the progression of breast cancer by serving as a post-transcriptional regulator of RNA processing and decay for its sense mRNA.

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A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression

Culbertson

Garcia

Markett

et al. 2021

Preprint

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Single cell kinetic modeling of redox-based drug metabolism in head and neck squamous cell carcinoma

Raddatz

Furdui

Bey

et al. 2022

Preprint

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Head and neck squamous cell carcinoma (HNSCC) cells are highly heterogeneous in their metabolism and typically experience elevated reactive oxygen species (ROS) levels in the tumor microenvironment. The tumor cells survive under these chronic oxidative conditions by upregulating antioxidant systems compared to healthy cells. Radiation and the majority of chemotherapies used clinically for treatment of HNSCC rely directly or indirectly upon the generation of short-lived ROS to induce cancer cell death. To investigate the heterogeneity of cellular responses to chemotherapeutic ROS generation in tumor and healthy tissue, we leveraged single cell RNA-sequencing (scRNA-seq) data to perform redox systems-level simulations of quinone-cycling β-lapachone treatment as a source of NQO1-dependent rapid superoxide and hydrogen peroxide (H2O2) production. Transcriptomic data from 10 HNSCC patient tumors was used to populate over 4000 single cell antioxidant enzymatic models. The simulations reflected significant systems-level differences between the redox states of healthy and cancer cells, demonstrating in some patient samples a targetable cancer cell population or in others statistically indistinguishable effects between non-malignant and malignant cells. Subsequent multivariate analyses between healthy and malignant cellular models point to distinct contributors of redox responses between these phenotypes. This model framework provides a mechanistic basis for explaining mixed outcomes of NQO1-bioactivatable therapeutics despite the tumor specificity of these drugs as defined by NQO1/catalase expression.

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IB-DNQ and Rucaparib dual treatment alters cell cycle regulation and DNA repair in triple negative breast cancer cells

Runnebohm,

Wijeratne,

Peck Justice

et al. 2024

Preprint

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Background: Triple negative breast cancer (TNBC), characterized by the lack of three canonical receptors, is unresponsive to commonly used hormonal therapies. One potential TNBC-specific therapeutic target is NQO1, as it is highly expressed in many TNBC patients and lowly expressed in non-cancer tissues. DNA damage induced by NQO1 bioactivatable drugs in combination with Rucaparib-mediated inhibition of PARP1-dependent DNA repair synergistically induces cell death. Methods: To gain a better understanding of the mechanisms behind this synergistic effect, we used global proteomics, phosphoproteomics, and thermal proteome profiling to analyze changes in protein abundance, phosphorylation and protein thermal stability. Results: Very few protein abundance changes resulted from single or dual agent treatment; however, protein phosphorylation and thermal stability were impacted. Histone H2AX was among several proteins identified to have increased phosphorylation when cells were treated with the combination of IB-DNQ and Rucaparib, validating that the drugs induced persistent DNA damage. Thermal proteome profiling revealed destabilization of H2AX following combination treatment, potentially a result of the increase in phosphorylation. Kinase substrate enrichment analysis predicted altered activity for kinases involved in DNA repair and cell cycle following dual agent treatment. Further biophysical analysis of these two processes revealed alterations in SWI/SNF complex association and tubulin / p53 interactions. Conclusions: Our findings that the drugs target DNA repair and cell cycle regulation, canonical cancer treatment targets, in a way that is dependent on increased expression of a protein selectively found to be upregulated in cancers without impacting protein abundance illustrate that multi-omics methodologies are important to gain a deeper understanding of the mechanisms behind treatment induced cancer cell death.

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Abstract 3038: Delineating the role of Arid3B in normal and malignant differentiation of esophageal and cervical stratified squamous epithelia

Cited by 4 publications

References 0 publications

A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression

A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression

Single cell kinetic modeling of redox-based drug metabolism in head and neck squamous cell carcinoma

IB-DNQ and Rucaparib dual treatment alters cell cycle regulation and DNA repair in triple negative breast cancer cells

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