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

Bruce Culbertson; Kristle Garcia; Daniel Markett; Hosseinali Asgharian; Li Chen; Lisa Fish; Albertas Navickas; Johnny Yu; Brian Woo; Arjun Scott Nanda; Benedict Choi; Shaopu Zhou; Joshua Rabinowitz; Hani Goodarzi

doi:10.1038/s43018-023-00554-7

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

Nat Cancer. 2023 May;4(5):682-698. doi: 10.1038/s43018-023-00554-7. Epub 2023 May 11.

Authors

Bruce Culbertson^#^{1

2

3

4}, Kristle Garcia^#^{1

2

3

4}, Daniel Markett^{1

2

3

4}, Hosseinali Asgharian^{1

2

3

4}, Li Chen⁵, Lisa Fish^{1

2

3

4}, Albertas Navickas^{1

2

3

4}, Johnny Yu^{1

2

3

4}, Brian Woo^{1

2

3

4}, Arjun Scott Nanda^{1

2

3

4}, Benedict Choi^{1

2

3}, Shaopu Zhou^{1

2

3}, Joshua Rabinowitz^{6

7}, Hani Goodarzi^{8

9

10

11}

Affiliations

¹ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
² Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁴ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
⁵ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, China.
⁶ Department of Chemistry, Lewis Sigler Institute for Integrative Genomics, Princeton, NJ, USA.
⁷ Ludwig Institute for Cancer Research, Princeton, NJ, USA.
⁸ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. [email protected].
⁹ Department of Urology, University of California, San Francisco, San Francisco, CA, USA. [email protected].
¹⁰ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. [email protected].
¹¹ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA. [email protected].

^# Contributed equally.

Abstract

Antisense RNAs are ubiquitous in human cells, yet their role is largely unexplored. Here we profiled antisense RNAs in the MDA-MB-231 breast cancer cell line and its highly lung metastatic derivative. We identified one antisense RNA that drives cancer progression by upregulating the redox enzyme NADPH quinone dehydrogenase 1 (NQO1), and named it NQO1-AS. Knockdown of either NQO1 or NQO1-AS reduced lung colonization in a mouse model, and investigation into the role of NQO1 indicated that it is broadly protective against oxidative damage and ferroptosis. Breast cancer cells in the lung are dependent on this pathway, and this dependence can be exploited therapeutically by inducing ferroptosis while inhibiting NQO1. Together, our findings establish a role for NQO1-AS in the progression of breast cancer by regulating its sense mRNA post-transcriptionally. Because breast cancer predominantly affects females, the disease models used in this study are of female origin and the results are primarily applicable to females.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms* / genetics
Female
Humans
Melanoma, Cutaneous Malignant
Mice
NAD(P)H Dehydrogenase (Quinone) / genetics
Neoplasms, Second Primary*
Quinones / metabolism
RNA, Antisense
Skin Neoplasms*

Substances

RNA, Antisense
Quinones
NQO1 protein, human
NAD(P)H Dehydrogenase (Quinone)

Abstract

Publication types

MeSH terms

Substances

Grants and funding