The role of the histone H3 variant CENPA in prostate cancer

Anjan K Saha,Rafael Contreras-Galindo,Yashar S Niknafs,Matthew Iyer,Tingting Qin,Karthik Padmanabhan,Javed Siddiqui,Monica Palande,Claire Wang,Brian Qian,Elizabeth Ward,Tara Tang,Scott A Tomlins,Scott D Gitlin,Maureen A Sartor,Gilbert S Omenn,Arul M Chinnaiyan,David M Markovitz

doi:10.1074/jbc.ra119.010080

Anjan K Saha, Rafael Contreras-Galindo + Show 16 more

Open Access

https://doi.org/10.1074/jbc.ra119.010080

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Abstract

Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients. Gain-of-function and loss-of-function experiments confirmed that CENPA promotes prostate cancer cell line growth. The results from the integrated sequencing experiments suggested a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Taken together, our findings show that CENPA overexpression is crucial to prostate cancer growth.

Highlights

Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized
Efforts to study human centromeres have focused on the epigenetics that drive centromere assembly [3, 4]. a-Satellite sequences that define centromere DNA are primarily occupied by a centromere-specific histone H3 variant known as centromere protein A (CENPA) [3, 5]
The centromeric histone H3 variant CENPA is overexpressed in cancer and has the propensity to localize to genomic loci that lie outside of the canonical centromere in the setting of overexpression

Summary

Introduction

Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. We first conducted a comparative analysis of CENPA expression relative to the remaining transcriptome in prostate cancer to identify associations with biological concepts that could computationally guide functional assessments.

Results

Conclusion