Transcription factors in prostate cancer progression

doi:10.3969/j.issn.1673-8640.2023.09.003

Abstract

Abstract:

Objective To investigate the 46 differentially expressed proteins of upstream transcriptional regulation mechanism in prostate cancer. Methods GeneGo MetaCore software and IPA software were used to conduct bioinformatics analysis on differential proteins and clarify the transcriptional regulatory network of these differential proteins. GEPIA2 database was used to analyze the expression level of identified transcription factors and their impacts on the survival of prostate cancer patients. Results Totally，20 transcriptional regulatory networks were identified. According to the enrichment of differentially expressed proteins，the top 6 networks were screened out to be regulated by 6 transcription factors，specificity protein 1（SP1），p53，Yin-Yang 1（YY1），androgen receptor（AR），c-Myc and Slug. Kaplan-Meier survival curve analysis showed that prostate cancer patients with high expression of p53 had long disease-free survival and overall survival compared to patients with low expression of p53（P=0.047 and 0.019，respectively）. The disease-free survival of prostate cancer patients with low expression of AR was longer than that of patients with high expression of AR（P=0.023）. The other 4 transcription factors had no impact on the prognosis of prostate cancer patients（P>0.05）. IPA software analysis results showed that SP1，p53，YY1，AR and c-Myc were regulated by epigallocatechin gallate（EGCG），protein kinase B（AKT）1，fibroblast growth factor 2（FGF2） and beta-estradiol regulation. Conclusions By analyzing the transcriptional regulatory network of 46 prostate cancer differentially expressed proteins，6 transcription factors and 4 upstream regulatory molecules related to prostate cancer have been found，which can provide new targets for early screening and prognostic evaluation of prostate cancer.

Key words: Proteomics, Transcription factor, Transcription regulation, Prostate cancer

CLC Number:

R446.1

SUN Chuanyu, ZHAO Xiaojun, GE Shengyang, ZHANG Yang. Transcription factors in prostate cancer progression[J]. Laboratory Medicine, 2023, 38(9): 818-824.

Figures/Tables 6

References 32

[1]	SIEGEL R L, MILLER K D, FUCHS H E, et al. Cancer statistics,2022[J]. CA Cancer J Clin, 2022, 72(1):7-33. DOI URL
[2]	GE S, MI Y, ZHAO X, et al. Characterization and validation of long noncoding RNAs as new candidates in prostate cancer[J]. Cancer Cell Int, 2020, 20(1):531. DOI PMID
[3]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020:globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. DOI URL
[4]	CHEN Q, FU L, HU J, et al. Silencing of PSMC2 inhibits development and metastasis of prostate cancer through regulating proliferation,apoptosis and migration[J]. Cancer Cell Int, 2021, 21(1):235. DOI
[5]	AFFRONTI H C, ROWSAM A M, PELLERITE A J, et al. Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy[J]. Nat Commun, 2020, 11(1):52. DOI PMID
[6]	LONG P, ZHANG L, HUANG B, et al. Integrating genome sequence and structural data for statistical learning to predict transcription factor binding sites[J]. Nucleic Acids Res, 2020, 48(22):12604-12617. DOI PMID
[7]	YANG M, HUANG W, SUN Y, et al. Prognosis and modulation mechanisms of COMMD6 in human tumours based on expression profiling and comprehensive bioinformatics analysis[J]. Br J Cancer, 2019, 121(8):699-709. DOI
[8]	GONDANE A, GIRMAY S, HELEVÄ A, et al. O-GlcNAc transferase couples MRE11 to transcriptionally active chromatin to suppress DNA damage[J]. J Biomed Sci, 2022, 29(1):13. DOI PMID
[9]	LOU S, LI T, KONG X, et al. TopicNet:a framework for measuring transcriptional regulatory network change[J]. Bioinformatics, 2020, 36(Suppl 1):i474-i481. DOI URL
[10]	SUN C Y, MI Y Y, GE S Y, et al. Tumor- and osteoblast-derived periostin in prostate cancer bone metastases[J]. Front Oncol, 2022, 11:795712. DOI URL
[11]	SUN C, SONG C, MA Z, et al. Periostin identified as a potential biomarker of prostate cancer by iTRAQ-proteomics analysis of prostate biopsy[J]. Proteome Sci, 2011, 9:22. DOI PMID
[12]	SUN Y, XU K, HE M, et al. Overexpression of glypican 5(GPC5) inhibits prostate cancer cell proliferation and invasion via suppressing Sp1-mediated EMT and activation of Wnt/β-catenin signaling[J]. Oncol Res, 2018, 26(4):565-572. DOI URL
[13]	KANG D, ZUO W, WU Q, et al. Inhibition of specificity protein 1 is involved in phloretin-induced suppression of prostate cancer[J]. Biomed Res Int, 2020, 2020:1358674.
[14]	HAN D S, LEE E O. Sp1 plays a key role in vasculogenic mimicry of human prostate cancer cells[J]. Int J Mol Sci, 2022, 23(3):1321. DOI URL
[15]	TAKAYAMA K I, SUZUKI T, FUJIMURA T, et al. Association of USP 10 with G3BP2 inhibits p53 signaling and contributes to poor outcome in prostate cancer[J]. Mol Cancer Res, 2018, 16(5):846-856. DOI URL
[16]	ASHIKARI D, TAKAYAMA K, TANAKA T, et al. Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer[J]. Oncogene, 2017, 36(45):6272-6281. DOI PMID
[17]	PASCAL L E, WANG Y, ZHONG M, et al. EAF2 and p53 co-regulate STAT3 activation in prostate cancer[J]. Neoplasia, 2018, 20(4):351-363. DOI PMID
[18]	SARVAGALLA S, KOLAPALLI S P, VALLABHAPURAPU S. The two sides of YY1 in cancer:a friend and a foe[J]. Front Oncol, 2019, 9:1230. DOI URL
[19]	XU C, TSAI Y H, GALBO P M, et al. Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer[J]. Nucleic Acids Res, 2021, 49(9):4971-4988. DOI PMID
[20]	CAMACHO-MOCTEZUMA B, QUEVEDO-CASTILLO M, MELENDEZ-ZAJGLA J, et al. YY1 negatively regulates the XAF1 gene expression in prostate cancer[J]. Biochem Biophys Res Commun, 2019, 508(3):973-979. DOI URL
[21]	LU C, BROWN L C, ANTONARAKIS E S, et al. Androgen receptor variant-driven prostate cancer Ⅱ:advances in laboratory investigations[J]. Prostate Cancer Prostatic Dis, 2020, 23(3):381-397. DOI
[22]	FRAME F M, MAITLAND N J. Epigenetic control of gene expression in the normal and malignant human prostate:a rapid response which promotes therapeutic resistance[J]. Int J Mol Sci, 2019, 20(10):2437. DOI URL
[23]	NANDA J S, AWADALLAH W N, KOHRT S E, et al. Increased nuclear factor I/B expression in prostate cancer correlates with AR expression[J]. Prostate, 2020, 80(13):1058-1070. DOI PMID
[24]	SHORNING B Y, DASS M S, SMALLEY M J, et al. The PI3K-AKT-mTOR pathway and prostate cancer:at the crossroads of AR,MAPK,and WNT signaling[J]. Int J Mol Sci, 2020, 21(12):4507. DOI URL
[25]	LABBÉ D P, ZADRA G, YANG M, et al. High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program[J]. Nat Commun, 2019, 10(1):4358. DOI PMID
[26]	LABBÉ D P, BROWN M. Transcriptional regulation in prostate cancer[J]. Cold Spring Harb Perspect Med, 2018, 8(11):a030437. DOI URL
[27]	MICKOVA A, KHARAISHVILI G, KURFURSTOVA D, et al. Skp2 and Slug are coexpressed in aggressive prostate cancer and inhibited by neddylation blockade[J]. Int J Mol Sci, 2021, 22(6):2844. DOI URL
[28]	IWASAKI K, NINOMIYA R, SHIN T, et al. Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1[J]. Cancer Sci, 2018, 109(10):3159-3170. DOI URL
[29]	MARCHETTI C, GAVAZZO P, BURLANDO B. Epigallocatechin-3-gallate mobilizes intracellular Ca²⁺ in prostate cancer cells through combined Ca²⁺ entry and Ca²⁺-induced Ca²⁺ release[J]. Life Sci, 2020, 258:118232. DOI URL
[30]	KHODAYARI MOEZ E, PYNE S, DINU I. Association between bivariate expression of key oncogenes and metabolic phenotypes of patients with prostate cancer[J]. Comput Biol Med, 2018, 103:55-63. DOI PMID
[31]	VASILEIOU C, BEFANI C, DIMAS K, et al. FGF-2 and HGF reverse abiraterone's effect οn intracellular levels of DHT in androgen-dependent and androgen independent prostate cancer cell lines[J]. J BUON, 2020, 25(2):1141-1147. PMID
[32]	DI ZAZZO E, GALASSO G, GIOVANNELLI P, et al. Estrogens and their receptors in prostate cancer:therapeutic implications[J]. Front Oncol, 2018, 8:2. DOI URL

蛋白编号	蛋白名称	肽段（95%）	116∶114^①
P62241	40S核糖体蛋白S8	2	1.53
P31943	异质核糖核蛋白H	3	2.17
P11021	GRP78^②	27	2.21
P09669	细胞色素C氧化酶6抗体	2	2.38
P10606	细胞色素c氧化酶亚单位5B，线粒体	7	2.70
P06576	ATP合酶β亚单位，线粒体	13	2.83
P38646	应激70蛋白，线粒体	11	2.91
P21810	二聚糖	19	2.97
P49411	延伸因子Tu，线粒体	6	3.02
P22314	泛素样修饰活化酶1	5	3.34
P13667	蛋白二硫化物异构酶A4	5	3.77
Q5SSJ5	异染色质蛋白1-结合蛋白3	5	4.06
P55327	肿瘤蛋白D52	3	4.25
Q99623	抗增殖蛋白2	3	4.57
P07237	蛋白质二硫化物异构酶	17	4.70
Q9NZN4	EH结构域蛋白2	2	5.55
P10809	HSP60^③，线粒体	25	5.97
P06748	核磷胺	10	7.94
Q15063	成骨细胞特异性因子2	13	9.12
Q00796	山梨醇脱氢酶	9	9.82

蛋白编号	蛋白名称	肽段（95%）	116∶114^①
P62241	40S核糖体蛋白S8	2	1.53
P31943	异质核糖核蛋白H	3	2.17
P11021	GRP78^②	27	2.21
P09669	细胞色素C氧化酶6抗体	2	2.38
P10606	细胞色素c氧化酶亚单位5B，线粒体	7	2.70
P06576	ATP合酶β亚单位，线粒体	13	2.83
P38646	应激70蛋白，线粒体	11	2.91
P21810	二聚糖	19	2.97
P49411	延伸因子Tu，线粒体	6	3.02
P22314	泛素样修饰活化酶1	5	3.34
P13667	蛋白二硫化物异构酶A4	5	3.77
Q5SSJ5	异染色质蛋白1-结合蛋白3	5	4.06
P55327	肿瘤蛋白D52	3	4.25
Q99623	抗增殖蛋白2	3	4.57
P07237	蛋白质二硫化物异构酶	17	4.70
Q9NZN4	EH结构域蛋白2	2	5.55
P10809	HSP60^③，线粒体	25	5.97
P06748	核磷胺	10	7.94
Q15063	成骨细胞特异性因子2	13	9.12
Q00796	山梨醇脱氢酶	9	9.82

蛋白编号	蛋白名称	肽段（95%）	116∶114
P17661	结蛋白	62	0.03
O95810	血清剥夺反应蛋白3	3	0.13
Q9BX66	SORBS1	18	0.18
P08670	波形蛋白	65	0.19
P51911	钙调蛋白-1	43	0.20
P04792	β-1热休克蛋白	15	0.22
P63267	γ-肠平滑肌肌动蛋白	191	0.24
Q969G5	蛋白激酶C δ结合蛋白	6	0.24
P12109	胶原蛋白α-1（Ⅵ）链	19	0.25
P11047	γ-1层黏连蛋白	9	0.28
O94875	SORBS2	2	0.32
P24821	肌腱蛋白	7	0.35
Q15942	Zyxin	4	0.35
Q9Y490	Talin-1	21	0.36
P02452	α-1（Ⅰ）链胶原蛋白	92	0.38
P18206	黏着斑蛋白	15	0.39
P20774	Mimecan	6	0.40
Q93052	脂肪瘤相关抗体	12	0.41
Q09666	神经细胞分化相关蛋白	62	0.42
P07585	核心蛋白聚糖	12	0.43
P98160	基底膜特异性硫酸乙酰肝素蛋白聚糖核心蛋白	17	0.44
P30086	磷脂酰乙醇胺结合蛋白1	7	0.47
P06396	凝溶胶蛋白	20	0.49
P12111	胶原蛋白α-3（Ⅵ）链	63	0.50
P01834	Ig κ链C区	4	0.54
P10909	簇集蛋白	3	0.54

蛋白编号	蛋白名称	肽段（95%）	116∶114
P17661	结蛋白	62	0.03
O95810	血清剥夺反应蛋白3	3	0.13
Q9BX66	SORBS1	18	0.18
P08670	波形蛋白	65	0.19
P51911	钙调蛋白-1	43	0.20
P04792	β-1热休克蛋白	15	0.22
P63267	γ-肠平滑肌肌动蛋白	191	0.24
Q969G5	蛋白激酶C δ结合蛋白	6	0.24
P12109	胶原蛋白α-1（Ⅵ）链	19	0.25
P11047	γ-1层黏连蛋白	9	0.28
O94875	SORBS2	2	0.32
P24821	肌腱蛋白	7	0.35
Q15942	Zyxin	4	0.35
Q9Y490	Talin-1	21	0.36
P02452	α-1（Ⅰ）链胶原蛋白	92	0.38
P18206	黏着斑蛋白	15	0.39
P20774	Mimecan	6	0.40
Q93052	脂肪瘤相关抗体	12	0.41
Q09666	神经细胞分化相关蛋白	62	0.42
P07585	核心蛋白聚糖	12	0.43
P98160	基底膜特异性硫酸乙酰肝素蛋白聚糖核心蛋白	17	0.44
P30086	磷脂酰乙醇胺结合蛋白1	7	0.47
P06396	凝溶胶蛋白	20	0.49
P12111	胶原蛋白α-3（Ⅵ）链	63	0.50
P01834	Ig κ链C区	4	0.54
P10909	簇集蛋白	3	0.54

序号	转录因子	GO富集生物过程	总节点数/个	根节点数/个	P值
1	SP1	细胞组分转移、细胞黏附调控、生物特性调控	19	18	9.23×10^-57
2	p53	细胞凋亡的负调控	11	10	4.70×10^-31
3	YY1	细胞、器官发育、生物过程的负调控，细胞黏附的负调控	10	9	6.55×10^-28
4	AR	细胞凋亡负调控，抑制细胞增殖	8	7	1.14×10^-21
5	c-Myc	细胞凋亡负调控，Caspase^②活性调节	8	7	1.14×10^-21
6	Slug	生物过程的负调节，参与氧化应激反应	48	28	1.12×10^-78