Integrative identification of non-coding regulatory regions driving metastatic prostate cancer

Brian J Woo; Ruhollah Moussavi-Baygi; Heather Karner; Mehran Karimzadeh; Hassan Yousefi; Sean Lee; Kristle Garcia; Tanvi Joshi; Keyi Yin; Albertas Navickas; Luke A Gilbert; Bo Wang; Hosseinali Asgharian; Felix Y Feng; Hani Goodarzi

doi:10.1016/j.celrep.2024.114764

Integrative identification of non-coding regulatory regions driving metastatic prostate cancer

Cell Rep. 2024 Sep 24;43(9):114764. doi: 10.1016/j.celrep.2024.114764. Epub 2024 Sep 13.

Authors

Affiliations

¹ Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Arc Institute, Palo Alto, CA 94305, USA.
² Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Vector Institute, Toronto, ON, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada; Arc Institute, Palo Alto, CA 94305, USA.
⁴ Vector Institute, Toronto, ON, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
⁵ Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].
⁶ Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].
⁷ Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Arc Institute, Palo Alto, CA 94305, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].

Abstract

Large-scale sequencing efforts have been undertaken to understand the mutational landscape of the coding genome. However, the vast majority of variants occur within non-coding genomic regions. We designed an integrative computational and experimental framework to identify recurrently mutated non-coding regulatory regions that drive tumor progression. Applying this framework to sequencing data from a large prostate cancer patient cohort revealed a large set of candidate drivers. We used (1) in silico analyses, (2) massively parallel reporter assays, and (3) in vivo CRISPR interference screens to systematically validate metastatic castration-resistant prostate cancer (mCRPC) drivers. One identified enhancer region, GH22I030351, acts on a bidirectional promoter to simultaneously modulate expression of the U2-associated splicing factor SF3A1 and chromosomal protein CCDC157. SF3A1 and CCDC157 promote tumor growth in vivo. We nominated a number of transcription factors, notably SOX6, to regulate expression of SF3A1 and CCDC157. Our integrative approach enables the systematic detection of non-coding regulatory regions that drive human cancers.

Keywords: CP: Cancer; CP: Molecular biology; bidirectional; genomics; modeling; noncoding.

MeSH terms

Animals
Cell Line, Tumor
Enhancer Elements, Genetic / genetics
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Mutation / genetics
Neoplasm Metastasis
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Prostatic Neoplasms, Castration-Resistant / genetics
Prostatic Neoplasms, Castration-Resistant / metabolism
Prostatic Neoplasms, Castration-Resistant / pathology
RNA Splicing Factors* / genetics
RNA Splicing Factors* / metabolism
Regulatory Sequences, Nucleic Acid / genetics

Substances

RNA Splicing Factors

Abstract

MeSH terms

Substances

Grants and funding