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

Abstract

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.

Gene-Expression Patterns of Tumor and Peritumor Tissues of Smoking and Non-Smoking HPV-Negative Patients with Head and Neck Squamous Cell Carcinoma

“…It is assumed that it functions as a tumor-suppressor gene in several human cancer types: decreased expression level of PITX1 is observed in various malignant tumors, e.g., HNSCC [ 48 , 49 ], gastric cancer [ 50 ], lung cancer [ 51 ], and colorectal carcinoma [ 52 ]. However, there is contrary evidence that PITX1 expression is upregulated in breast cancer [ 53 , 54 ], prostate cancer [ 55 ], and lung cancer [ 56 ]. Thus, PITX1 expression is tumor-type-specific.…”

ANS: Adjusted Neighborhood Scoring to improve assessment of gene signatures in single-cell RNA-seq data

“…Previous research on PITX1 in cancer has revealed cancer-type-specific effects. While upregulation of PITX1 has been shown to be associated with tumor progression in lung adenocarcinoma 31 , kidney renal clear cell carcinoma 32 , breast 33 , epithelial ovarian 34 , and prostate 35 cancer, interestingly, in other cancer types, such as melanoma 36 , ESCC 37 , osteosarcoma 38 and head and neck squamous cell carcinoma 39 , down-regulation of PITX1 has been found to enhance tumor progression. Other EMT-related genes exclusively present in our signature included two long-non-coding RNA genes: ABHD11-AS1 and BCYRN1 .…”

Predicting prostate adenocarcinoma patients’ survival and immune signature: a novel risk model based on telomere-related genes

“…Baena et al observed that increased TERC expression was associated with a poorer prognosis in patients with PRAD [ 16 ]. Furthermore, Poos et al found that the expression levels of PITX1, a transcription factor that regulates TERC, increased with increasing levels of Ki67 in PRAD, indicating a poorer clinical outcome [ 17 , 18 ].…”