MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

Nichelle C Whitlock,Ross Lake,Adam G Sowalsky,Rayann Atway,Huihui Ye,Scott Wilkinson,Elizabeth D Walton,Nicole V Carrabba,Brian J Capaldo,Nicholas T Terrigino,Shana Y Trostel,S Thomas Hennigan,Berkley E Gryder

doi:10.1038/s41388-020-01389-7

Nichelle C Whitlock, Ross Lake + Show 11 more

Open Access

https://doi.org/10.1038/s41388-020-01389-7

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Abstract

Localized prostate cancer develops very slowly in most men, with the androgen receptor (AR) and MYC transcription factors amongst the most well-characterized drivers of prostate tumorigenesis. Canonically, MYC up-regulation in luminal prostate cancer cells functions to oppose the terminally differentiating effects of AR. However, the effects of MYC up-regulation are pleiotropic and inconsistent with a poorly proliferative phenotype. Here we show that increased MYC expression and activity are associated with the down-regulation of MEIS1, a HOX-family transcription factor. Using RNA-seq to profile a series of human prostate cancer specimens laser capture microdissected on the basis of MYC immunohistochemistry, MYC activity, and MEIS1 expression were inversely correlated. Knockdown of MYC expression in prostate cancer cells increased the expression of MEIS1 and increased the occupancy of MYC at the MEIS1 locus. Finally, we show in laser capture microdissected human prostate cancer samples and the prostate TCGA cohort that MEIS1 expression is inversely proportional to AR activity as well as HOXB13, a known interacting protein of both AR and MEIS1. Collectively, our data demonstrate that elevated MYC in a subset of primary prostate cancers functions in a negative role in regulating MEIS1 expression, and that this down-regulation may contribute to MYC-driven development and progression.

Highlights

Advanced prostate cancers harbor a limited number of recurrently altered genes whose expression change at the earliest stages of tumor development
MYC activity is weakly associated with proliferation in primary prostate cancer MYC orchestrates a broad range of biological functions, it has been shown in many cancers that MYC
We used transcriptome profiling to assess subpopulations of prostate tumors based on differential MYC protein expression and MYC activity, and we compared differentially expressed genes and pathways within the larger prostate TCGA cohort based on MYC activity

Summary

Introduction

Advanced prostate cancers harbor a limited number of recurrently altered genes whose expression change at the earliest stages of tumor development. RNA, increased purine metabolism, and expression of the telomere RNA subunit TERC [12,13,14] These effects contrast sharply with the phenotype of highly amplified MYC, which is enriched in metastatic and treatment-resistant prostate cancers, LNCaP/ LNCaP/ LNCaP/ LNCaP/. Data represents mean ± standard deviation of three independent experiments conducted in triplicate, with open circles representing individual replicate RNA quantity values (****P < 0.0001 for each cell line vs control by two-way ANOVA). We sought to examine the genetic contribution of MYC to the development and progression of primary PCa in the context of dysregulated growth by using anti-MYC immunohistochemistry (IHC) and performing laser capture microdissection on populations of human prostate tumor cells with varying expression of MYC protein. MYC binding to the MEIS1 locus decreases as MYC levels increase, and that MEIS1 expression is negatively correlated with HOXB13 expression and AR activity

Results

Discussion

Materials and methods

Compliance with ethical standards

Cancer