PUM1 represses CDKN1B translation and contributes to prostate cancer progression

Mapping Intimacies ◽

10.1101/2021.05.27.21257930 ◽

2021 ◽

Author(s):

Eugene Yujun Xu

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Protein Expression ◽

Cancer Cell ◽

Cancer Progression ◽

Translational Control ◽

Rna Binding ◽

Prostate Cancer Cell ◽

Mrna Level ◽

Critical Role

Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis; identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics. Highly conserved RNA binding protein PUM1 regulates mouse growth and cell proliferation, propelling us to examine its role in cancer. We found human PUM1 is highly expressed in a diverse group of cancer, including prostate cancer; enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients. Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels. Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation, and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size. Downregulation of PUM1 in prostate cancer cells consistently elevated CDKN1B protein expression through increased translation but did not impact its mRNA level, while overexpression of PUM1 reduced CDKN1B protein level. Our finding established a critical role of PUM1 mediated translational control, particularly the PUM1-CDKN1B axis, in prostate cancer cell growth and tumorigenesis. We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and could be potential targets for therapeutics development.

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How can food extracts consumed in the Mediterranean and East Asia suppress prostate cancer proliferation?

British Journal Of Nutrition ◽

10.1017/s0007114511005770 ◽

2011 ◽

Vol 108 (3) ◽

pp. 424-430 ◽

Cited By ~ 4

Author(s):

Mu Yao ◽

Chanlu Xie ◽

Maryrose Constantine ◽

Sheng Hua ◽

Brett D. Hambly ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

East Asia ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Prostate Cancer Cell ◽

Cancer Cell Proliferation ◽

Prostate Cancer Cells ◽

The Mediterranean

We have developed a blend of food extracts commonly consumed in the Mediterranean and East Asia, named blueberry punch (BBP), with the ultimate aim to formulate a chemoprevention strategy to inhibit prostate cancer progression in men on active surveillance protocol. We demonstrated previously that BBP inhibited prostate cancer cell proliferation in vitro and in vivo. The purpose of this study was to determine the molecular mechanism responsible for the suppression of prostate cancer cell proliferation by BBP. Treatment of lymph node-metastasised prostate cancer cells (LNCaP) and bone-metastasised prostate cancer cells (PC-3 and MDA-PCa-2b) with BBP (up to 0·8 %) for 72 h increased the percentage of cells at the G0/G1 phase and decreased those at the S and G2/M phases. The finding was supported by the reduction in the percentage of Ki-67-positive cells and of DNA synthesis measured by the incorporation of 5-ethynyl-2′-deoxyuridine. Concomitantly, BBP treatment decreased the protein levels of phosphorylated retinoblastoma, cyclin D1 and E, cyclin-dependent kinase (CDK) 4 and 2, and pre-replication complex (CDC6 and MCM7) in LNCaP and PC-3 cells, whereas CDK inhibitor p27 was elevated in these cell lines. In conclusion, BBP exerts its anti-proliferative effect on prostate cancer cells by modulating the expression and phosphorylation of multiple regulatory proteins essential for cell proliferation.

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Estrogen Receptors β1 and β2 Have Opposing Roles in Regulating Proliferation and Bone Metastasis Genes in the Prostate Cancer Cell Line PC3

Molecular Endocrinology ◽

10.1210/me.2012.1227 ◽

2012 ◽

Vol 26 (12) ◽

pp. 1991-2003 ◽

Cited By ~ 75

Author(s):

Prasenjit Dey ◽

Philip Jonsson ◽

Johan Hartman ◽

Cecilia Williams ◽

Anders Ström ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Cell ◽

Cancer Progression ◽

Prostate Cancer Cell ◽

Mrna Level ◽

Gleason Grade ◽

Mrna Levels ◽

Proliferation Markers ◽

Pc3 Cells

Abstract The estrogen receptor (ER)β1 is successively lost during cancer progression, whereas its splice variant, ERβ2, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERβ1 and/or the expression of ERβ2 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERβ1 or ERβ2, we found that the ERβ variants differentially regulate genes known to affect tumor behavior. We found that ERβ1 repressed the expression of the bone metastasis regulator Runx2 in PC3 cells. By contrast, RUNX2 expression was up-regulated at the mRNA level by ERβ2 in PC3 cells, whereas Slug was up-regulated by ERβ2 in both PC3 and 22Rv1 cells. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate carcinoma, was increased by ERβ2. In agreement with the increased Twist1 expression, we found increased expression of Dickkopf homolog 1; Dickkopf homolog 1 is a factor that has been shown to increase the RANK ligand/osteoprotegerin ratio and enhance osteoclastogenesis, indicating that the expression of ERβ2 can cause osteolytic cancer. Furthermore, we found that only ERβ1 inhibited proliferation, whereas ERβ2 increased proliferation. The expression of the proliferation markers Cyclin E, c-Myc, and p45Skp2 was differentially affected by ERβ1 and ERβ2 expression. In addition, nuclear β-catenin protein and its mRNA levels were reduced by ERβ1 expression. In conclusion, we found that ERβ1 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERβ2 increased proliferation and up-regulated factors involved in bone metastasis. Thus, in prostate cancer cells, ERβ2 has oncogenic abilities that are in strong contrast to the tumor-suppressing effects of ERβ1.

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Targeting the Lnc-OPHN1-5/androgen receptor/hnRNPA1 complex increases Enzalutamide sensitivity to better suppress prostate cancer progression

Cell Death and Disease ◽

10.1038/s41419-021-03966-4 ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Meng Zhang ◽

Yin Sun ◽

Chi-Ping Huang ◽

Jie Luo ◽

Li Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Protein Expression ◽

Cancer Progression ◽

Translational Control ◽

Rna Binding ◽

Formation Rate ◽

Tumor Formation ◽

Clinical Samples ◽

Control Group

AbstractLong non-coding RNAs (lncRNAs) have been found to play critical roles in regulating gene expression, but their function in translational control is poorly understood. We found lnc-OPHN1-5, which lies close to the androgen receptor (AR) gene on chromosome X, increased prostate cancer (PCa) Enzalutamide (Enz) sensitivity via decreasing AR protein expression and associated activity. Mechanism dissection revealed that lnc-OPHN1-5 interacted with AR-mRNA to minimize its interaction with the RNA binding protein (RBP) hnRNPA1. Suppressing lnc-OPHN1-5 expression promoted the interaction between AR-mRNA and hnRNPA1, followed by an increase of ribosome association with AR-mRNA and translation. This effect was reversed by increasing lnc-OPHN1-5 expression. Consistently, the in vivo mice model confirmed that knocking down lnc-OPHN1-5 expression in tumors significantly increased the tumor formation rate and AR protein expression compared with the control group. Furthermore, knocking down hnRNPA1 blocked/reversed shlnc-OPHN1-5-increased AR protein expression and re-sensitized cells to Enz treatment efficacy. Evidence from Enz-resistant cell lines, patient-derived xenograft (PDX) models, clinical samples, and a human PCa study accordantly suggested that patients with low expression of lnc-OPHN1-5 likely have unfavorable prognoses and probably are less sensitive to Enz treatment. In summary, targeting this newly identified lnc-OPHN1-5/AR/hnRNPA1 complex may help develop novel therapies to increase Enz treatment sensitivity for suppressing the PCa at an advanced stage.

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Exendin-4, a Glucagon-Like Peptide-1 Receptor Agonist, Attenuates Prostate Cancer Cell Proliferation via Phosphorylation of MKP-1

Diabetes ◽

10.2337/db18-1957-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1957-P

Author(s):

TAKAKO KAWANAMI ◽

TAKASHI NOMIYAMA ◽

YURIKO HAMAGUCHI ◽

TOMOKO TANAKA ◽

TOSHIHIKO YANASE

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Receptor Agonist ◽

Prostate Cancer Cell ◽

Cancer Cell Proliferation ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Distinct roles for the RNA-binding protein Staufen1 in prostate cancer

BMC Cancer ◽

10.1186/s12885-021-07844-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kristen A. Marcellus ◽

Tara E. Crawford Parks ◽

Shekoufeh Almasi ◽

Bernard J. Jasmin

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Rna Binding ◽

Prostate Cancer Cell ◽

Rna Binding Protein ◽

Migration And Invasion ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Prostate Cells

Abstract Background Prostate cancer is one of the most common malignant cancers with the second highest global rate of mortality in men. During the early stages of disease progression, tumour growth is local and androgen-dependent. Despite treatment, a large percentage of patients develop androgen-independent prostate cancer, which often results in metastases, a leading cause of mortality in these patients. Our previous work on the RNA-binding protein Staufen1 demonstrated its novel role in cancer biology, and in particular rhabdomyosarcoma tumorigenesis. To build upon this work, we have focused on the role of Staufen1 in other forms of cancer and describe here the novel and differential roles of Staufen1 in prostate cancer. Methods Using a cell-based approach, three independent prostate cancer cell lines with different characteristics were used to evaluate the expression of Staufen1 in human prostate cancer relative to control prostate cells. The functional impact of Staufen1 on several key oncogenic features of prostate cancer cells including proliferation, apoptosis, migration and invasion were systematically investigated. Results We show that Staufen1 levels are increased in all human prostate cancer cells examined in comparison to normal prostate epithelial cells. Furthermore, Staufen1 differentially regulates growth, migration, and invasion in the various prostate cancer cells assessed. In LNCaP prostate cancer cells, Staufen1 regulates cell proliferation through mTOR activation. Conversely, Staufen1 regulates migration and invasion of the highly invasive, bone metastatic-derived, PC3 prostate cells via the activation of focal adhesion kinase. Conclusions Collectively, these results show that Staufen1 has a direct impact in prostate cancer development and further demonstrate that its functions vary amongst the prostate cancer cell types. Accordingly, Staufen1 represents a novel target for the development of much-needed therapeutic strategies for prostate cancer.

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