PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power.

Alexandra M Poos ,Markus Graefen,Neeraja Jaishankar,Aria Baniahmad,Caroline Knotz,Delia M Braun,Daniela Röll,Rainer Koenig,Karsten Rippe,Holger Erfle,Thomas Wollmann,Ronald Simon,Lukas Frank,Roman Spilger,Karl Rohr,Cornelia Schroeder,Guido Sauter,Inn Chung,Marcus Oswald,Christoph Fraune,Jan Meiners,Adam Polonski,Manuel Gunkel,Alexander T Stenzel ,Georgia Makrypidi‐Fraune

doi:10.3390/cancers14051267

Abstract

Simple SummaryMost prostate cancer is of an indolent form and is curable. However, some prostate cancer belongs to rather aggressive subtypes leading to metastasis and death, and immediate therapy is mandatory. However, for these, the therapeutic options are highly invasive, such as radical prostatectomy, radiation or brachytherapy. Hence, a precise diagnosis of these tumor subtypes is needed, and the thus far applied diagnostic means are insufficient for this. Besides this, for their endless cell divisions, prostate cancer cells need the enzyme telomerase to elongate their telomeres (chromatin endings). In this study, we developed a gene regulatory model based on large data from transcription profiles from prostate cancer and chromatin-immuno-precipitation studies. We identified the developmental regulator PITX1 regulating telomerase. Besides observing experimental evidence of PITX1′s functional role in telomerase regulation, we also found PITX1 serving as a prognostic marker, as concluded from an analysis of more than 15,000 prostate cancer samples.The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of TERT, transcription factors regulating TERT may suit as prognostic markers. To identify transcription factors regulating TERT, we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as TERT regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates TERT expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length.

Highlights

Prostate cancer (PCa) shows the second-highest incidence of cancer in men and is the fifth most frequent leading cause of cancer death [1]
Comparing the transcription factor (TF) frequencies in the models of tumors and healthy controls led to a list of 17 significant TF predicted to regulate telomerase reverse transcriptase (TERT) in prostate tumors (Table 1)
Comparing the models of prostate cancer (PCa) versus all other 18 cancer types led () to 17 TF being specific for TERT regulation in PCa (from the 17 regulators, androgen receptor (AR) and E2F2 were found in several other cancer entities (=common regulators)) (Table S2)

Summary

Introduction

Prostate cancer (PCa) shows the second-highest incidence of cancer in men and is the fifth most frequent leading cause of cancer death [1]. The suggested risk stratification combines Gleason score, pre-operative PSA-levels in the blood, and further pathological and clinical staging These measurements are insufficient to adequately predict the outcome of patients [6], making a surveillance strategy hazardous, if the prediction needs to be made before prostatectomy. Mutations (mainly ETS), epigenetic changes (e.g., DNA methylation changes upon IDH1 mutation), and androgen receptor (AR) activity, seven subtypes of primary PCa were specified by The Cancer Genome Atlas Research Network [3,4]. Such genetic subtyping does not lead to a mechanistic understanding of the patho-mechanisms. We improved risk stratification in PCa by identifying new biomarkers via a mechanism-based approach investigating the regulation of telomerase

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