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Supplementary figure and table legends

Additional Information on molecular analyses determining CHD1 and SPOP status

Sample overview

SPOP mutation identified in this cohort.

Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1-deleted/SPOP-mutated metastatic CRPC (mCRPC).Experimental Design: We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. SPOP status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses.Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with six of these mutations not reported previously in prostate cancer. SPOP mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 P = 0.001; CHD1: OR, 7.30, P = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, P = 0.002, CHD1: HR, 0.50, P = 0.06).Conclusions: SPOP-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment. Clin Cancer Res; 24(22); 5585–93. ©2018 AACR.

Combined SPOP/ CHD1 status and time/ response to abiraterone.

The most salient feature of carbon monoxide (CO)-mediated cytoprotection is the suppression of inflammation and cell death. One of the important cellular targets of CO is the macrophage (mφ). Many studies have shown that exposure of mφ to CO results in the generation of an antiinflammatory phenotype; however, these reports have ignored the effect of CO alone on the cell before stimulation. Most investigations have focused on the actions of CO in modulating the response to noxious stimuli. We demonstrate here that exposure of mφ to CO results in a significant and transient burst of reactive oxygen species (ROS) arising from the mitochondria (mitochondria-deficient mφ do not respond to CO to produce ROS). The ROS promote rapid activation and stabilization of the transcription factor hypoxia-inducible factor 1α (HIF-1α), which regulates expression of genes involved in inflammation, metabolism, and cell survival. The increase in HIF-1α expression induced by CO results in regulated expression of TGF-β, a potent antiinflammatory cytokine. CO-induced HIF-1α and TGF-β expression are necessary to prevent anoxia/reoxygenation-induced apoptosis in mφ. Furthermore, blockade of HIF-1α using RNA interference and HIF-1α- cre -lox mφ resulted in a loss of TGF-β expression and CO-induced protection. A similar mechanism of CO-induced protection was operational in vivo to protect against lung ischemia-reperfusion injury. Taken together, we conclude that CO conditions the mφ via a HIF-1α and TGF-β-dependent mechanism and we elucidate the earliest events in mφ signaling that lead to and preserve cellular homeostasis at the site of injury.

Emerging evidence suggests that chromatin adopts a non-random three dimensional (3D) topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further elucidation. To address these questions, we performed unbiased high-resolution mapping of intra- and inter-chromosome interactions upon over-expression of ERG, an oncogenic transcription factor frequently over-expressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding and gene expression, we demonstrate for the first time that an oncogenic transcription factor can induce global, reproducible and functionally coherent changes in chromatin organization. We also show using spectral karyotyping that ERG over-expression is associated with a specific translocation involving chromosomes 13 and 15 at loci that are enriched in ERG binding. The results presented here have broader implications, as many driving genetic lesions in other cancer types involve altered levels of transcription factors due to genomic alterations (e.g. EWS-FLI1, c-Myc, n-Myc, PML-RARα). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2222. doi:1538-7445.AM2012-2222

Background: Postoperative hemodynamic adverse severe events (PHASE, severe bradycardia and hypotension) can occur during recovery from spinal anesthesia. The incidence, contributing factors and consequences of