PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Gene Expression Data
2.2. The Mixed Integer Linear Model of TERT Regulation
2.3. Regulatory TF-TF Network
2.4. Immunohistochemical Analysis of PITX1 and IRF1 in PCa Patients
2.5. Cell Lines
2.6. siRNA Knockdown
2.7. Chromatin Immunoprecipitation
2.8. Statistical Analysis
3. Results
3.1. The Direct Model Predicts Specific Transcription Factors of TERT in PCa
3.2. Identifying a Regulatory Module for TERT Regulation in PCa
3.3. PCa Tissue Cells with A High PITX1 Protein Expression Show Higher Telomere Staining Intensity
3.4. In Vitro Experiments Showed That PITX1 Binds to the Promoter of TERT and PITX1 Knockdown Reduces TERT Expression
3.5. The Identified Transcription Factor PITX1 Suits as a Prognostic Marker
3.6. The Identified Transcription Factors IRF1, CTCF, and TFAP2D Also Suit as Prognostic Markers, Particularly when Combining them with PITX1
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Regulators Tumor | Frequency Tumor (n = 300 Models) | Frequency Normal (n = 300 Models) | p-Value ** |
---|---|---|---|
PITX1 * | 186 (62%) | 35 (12%) | 1.56 × 10−37 |
MITF * | 119 (40%) | 28 (9%) | 5.97 × 10−17 |
AR * | 92 (31%) | 21 (7%) | 1.26 × 10−12 |
TFAP2C * | 72 (24%) | 11 (4%) | 1.67 × 10−12 |
E2F2 * | 92 (31%) | 24 (8%) | 1.31 × 10−11 |
NR2F2 * | 97 (32%) | 27 (9%) | 1.31 × 10−11 |
SMARCB1 | 88 (29%) | 24 (8%) | 1.15 × 10−10 |
CEBPA * | 65 (22%) | 20 (7%) | 6.08 × 10−7 |
BHLHE40 * | 53 (18%) | 16 (5%) | 8.26 × 10−6 |
CTCF * | 48 (16%) | 15 (5%) | 4.13 × 10−5 |
ETS1 * | 63 (21%) | 26 (9%) | 7.43 × 10−5 |
MXI1 | 27 (9%) | 5 (2%) | 1.75 × 10−4 |
POLR2A | 34 (11%) | 9 (3%) | 2.23 × 10−4 |
RAD21 | 32 (11%) | 11 (4%) | 2.37 × 10−3 |
IRF1 * | 31 (10%) | 12 (4%) | 6.38 × 10−3 |
TFAP2D * | 34 (11%) | 18 (6%) | 3.91 × 10−2 |
MAX | 36 (12%) | 20 (7%) | 4.62 × 10−2 |
TERT Regulator | Regulators Used in At Least 20% of the Models | Number of Direct Regulators | Number of TERT Regulators |
---|---|---|---|
PITX1 | SMARCC1, TAF1 *, HEY1 *, POLR2A *, FOXO1, HNF4A, ESR1 *, RBBP5, SMAD1, SMARCB1 * | 10 | 5 |
AR | MAFF, MAFK, ZBTB17, CREB3, GATA2, TCF4, CTCF *, EGR1 * | 8 | 2 |
MITF | MXI1 *, ZNF263, SMC3, TAL1 *, MYC *, EP300, MAX * | 7 | 4 |
CTCF | MAX *, PRDM16, YY1, RBBP5, REST *, POU2F2 *, FOXP2, EP300 | 8 | 3 |
BHLHE40 | ARNTL, HIF1A *, SIN3AK20 *, EGR1 *, NCOR1, AR *, CEBPB, GABPA, ZNF143 | 9 | 4 |
ETS1 | ETV2, PAX5 *, FOS, CEBPB, USF1, FOXA1, TCF7L2, IRF4, GATA2 | 9 | 1 |
CEBPA | SP1, CLOCK, IKZF1 *, MYC *, NCOR1, FOXP2, JUN, SREBF1, MAZ * | 9 | 3 |
E2F2 | E2F4 *, PML, E2F7, MAFK, ELF1, HEY1 *, EBF1, E2F6 *, MAFF, TCF12 * | 10 | 4 |
NR2F2 | MXI1 *, TP53 *, USF1, E2F4 *, SF1, FOXP2, SIN3AK20 *, ZNF263 | 8 | 4 |
IRF1 | NFKB.P50.P65 *, IRF2, SPI1, EGR1 *, MYB * | 5 | 3 |
TFAP2C | TP63, MAX *, RAD21 *, RBPJ, SP1, POU5F1, ZFP36L1, MTA1, E2F1 *, EZH2, SETDB1 | 11 | 3 |
PITX1 | |||||
---|---|---|---|---|---|
Parameter | n Evaluable | Negative (%) | Low (%) | High (%) | p Value |
All cancers | 15,011 | 38.3 | 57.7 | 4.0 | |
Tumor stage | <0.0001 | ||||
pT2 | 9555 | 41.5 | 55.5 | 3.0 | |
pT3a | 3366 | 34.6 | 60.4 | 5.0 | |
pT3b-pT4 | 2030 | 30.0 | 63.0 | 7.0 | |
Gleason grade | <0.0001 | ||||
≤3 + 3 | 2794 | 41.8 | 55.3 | 2.8 | |
3 + 4 | 7971 | 40.2 | 56.5 | 3.3 | |
3 + 4 Tert.5 | 720 | 38.9 | 57.6 | 3.5 | |
4 + 3 | 1479 | 30.6 | 62.8 | 6.6 | |
4 + 3 Tert.5 | 1056 | 31.3 | 63.5 | 5.2 | |
≥4 + 4 | 867 | 28.7 | 61.5 | 9.8 | |
Lymph node metastasis | <0.0001 | ||||
N0 | 9067 | 37.7 | 58.0 | 4.3 | |
N+ | 1121 | 30.2 | 63.2 | 6.6 | |
Surgical margin | <0.0001 | ||||
negative | 11,973 | 39.2 | 57.1 | 3.7 | |
positive | 2985 | 35.1 | 59.8 | 5.1 |
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Poos, A.M.; Schroeder, C.; Jaishankar, N.; Röll, D.; Oswald, M.; Meiners, J.; Braun, D.M.; Knotz, C.; Frank, L.; Gunkel, M.; et al. PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power. Cancers 2022, 14, 1267. https://doi.org/10.3390/cancers14051267
Poos AM, Schroeder C, Jaishankar N, Röll D, Oswald M, Meiners J, Braun DM, Knotz C, Frank L, Gunkel M, et al. PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power. Cancers. 2022; 14(5):1267. https://doi.org/10.3390/cancers14051267
Chicago/Turabian StylePoos, Alexandra M., Cornelia Schroeder, Neeraja Jaishankar, Daniela Röll, Marcus Oswald, Jan Meiners, Delia M. Braun, Caroline Knotz, Lukas Frank, Manuel Gunkel, and et al. 2022. "PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power" Cancers 14, no. 5: 1267. https://doi.org/10.3390/cancers14051267