KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer

Xiong, Xiaozhong; Schöber, Markus; Tassone, Evelyne; Khodadadi‐Jamayran, Alireza; Sastre-Perona, Ana; Zhou, Hua; Tsirigos, Aristotelis; Shen, Steven S.; Chang, Miao; Melamed, Jonathan; Ossowski, Liliana; Wilson, E. Lynette

doi:10.1016/j.celrep.2018.11.065

Cited by 29 publications

(28 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In maintaining PCa stem cell homeostasis, mixed lineage kinase 3 (MLK-3), a MAPK member, promotes β-catenin's interacts with KLF4 instead of TCF, and finally reduces EMT initiation [150][151][152]. When in circulation, PCa cells need to overcome nutrient limits, which might cause tumor necrosis.…”

Section: How Ras/wnt Crosstalk Affect Pca Bmmentioning

confidence: 99%

Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis

2020

View full text Add to dashboard Cite

Prostate cancer (PCa) is one of the most prevalent and malignant cancer types in men, which causes more than three-hundred thousand cancer death each year. At late stage of PCa progression, bone marrow is the most often metastatic site that constitutes almost 70% of metastatic cases of the PCa population. However, the characteristic for the osteo-philic property of PCa is still puzzling. Recent studies reported that the Wnt and Ras signaling pathways are pivotal in bone metastasis and that take parts in different cytological changes, but their crosstalk is not well studied. In this review, we focused on interactions between the Wnt and Ras signaling pathways during each stage of bone metastasis and present the fate of those interactions. This review contributes insights that can guide other researchers by unveiling more details with regard to bone metastasis and might also help in finding potential therapeutic regimens for preventing PCa bone metastasis.

show abstract

Section: How Ras/wnt Crosstalk Affect Pca Bmmentioning

confidence: 99%

Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis

2020

View full text Add to dashboard Cite

show abstract

“…We also examined if upregulation of MED19 could promote the proliferation of other early stage prostate cancer cell lines. Indeed, we found that overexpression of MED19 increased proliferation (as well as colony formation) in non-malignant RWPE-1 cells (Fig 2A and S2A Fig), but did not affect the growth of RWPE-2 cells, which are a malignant derivative of RWPE-1 cells, transformed with RAS (Fig 2B and S2B Fig) [31]. This is in spite of similar levels of MED19 protein expressed in RWPE-1 cells and RWPE-2 cells (S3 Fig).…”

Section: Resultsmentioning

confidence: 99%

“…RWPE-1 cells and RWPE-2 cells were cultured in keratinocyte SFM media supplemented with L-glutamine, BPE, and EGF (ThermoFisher Scientific) [63]. The mouse prostate stem cell line expressing activated AKT was cultured as described in [31]. R1881 (Perkin Elmer) was reconstituted in ethanol.…”

Section: Methodsmentioning

confidence: 99%

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

Weber

Ruoff

Garabedian

2019

Preprint

View full text Add to dashboard Cite

Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined H3K27 acetylation genome-wide. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 and genomic sites occupied by MED19 and AR are enriched for ELK1, a transcription factor that binds the AR N-terminus to promote select AR-target gene expression. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.Author summaryProstate cancer is one of the most common cancers worldwide, and androgen hormones are essential for prostate cancer growth. Androgens exert their effects through a protein called the androgen receptor (AR), which turns on and off genes that regulate prostate cancer growth. Powerful drugs that block AR action by lowering androgen levels – so-called androgen deprivation therapy - are used to treat prostate cancer patients, and these yield initial success in reducing tumor growth. However, over time, tumors circumvent androgen deprivation therapy and patients relapse; in many cases, this occurs because AR becomes re-activated. The factors responsible for re-activating AR and promoting growth under androgen deprivation are not well understood. Here, we demonstrate that a subunit of the Mediator transcriptional regulatory complex, called MED19, promotes growth of prostate cancer cells under low androgen conditions, mimicking the ability of tumors to grow under androgen deprivation in prostate cancer patients. MED19 promotes androgen-independent growth by working with a transcription factor that interacts with AR, called ELK1, to induce the expression of genes regulated by AR that promote prostate cancer growth. This study provides important insight into how prostate cancer cells can maintain growth under androgen deprivation through MED19.

show abstract

“…Perhaps the above contradictions can be at least partially resolved by the discovery that the levels of KLF4 vary depending on the subtype of prostate cancer [ 100 ]. KLF4 is highly expressed in indolent tumors which do not cause any symptoms and do not require any treatment but is absent from aggressive prostate tumors.…”

Section: Prostate Cancermentioning

confidence: 99%

“…The reduced expression of KLF4 is associated with the molecular features of aggressive cancers. Accordingly, induction of KLF4 in established tumors reverses their aggressive phenotype [ 100 ]. KLF4 thus blocks the malignant transformation and impedes tumor progression.…”

Section: Prostate Cancermentioning

confidence: 99%

Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types

Taracha-Wisniewska

Kotarba

Dworkin

et al. 2020

IJMS

View full text Add to dashboard Cite

Krüppel-like factor 4 (KLF4) is a transcription factor highly conserved in evolution. It is particularly well known for its role in inducing pluripotent stem cells. In addition, KLF4 plays many roles in cancer. The results of most studies suggest that KLF4 is a tumor suppressor. However, the functioning of KLF4 is regulated at many levels. These include regulation of transcription, alternative splicing, miRNA, post-translational modifications, subcellular localization, protein stability and interactions with other molecules. Simple experiments aimed at assaying transcript levels or protein levels fail to address this complexity and thus may deliver misleading results. Tumor subtypes are also important; for example, in prostate cancer KLF4 is highly expressed in indolent tumors where it impedes tumor progression, while it is absent from aggressive prostate tumors. KLF4 is important in regulating response to many known drugs, and it also plays a role in tumor microenvironment. More and more information is available about upstream regulators, downstream targets and signaling pathways associated with the involvement of KLF4 in cancer. Furthermore, KLF4 performs critical function in the overall regulation of tissue homeostasis, cellular integrity, and progression towards malignancy. Here we summarize and analyze the latest findings concerning this fascinating transcription factor.

show abstract

KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer

Cited by 29 publications

References 69 publications

Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis

Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types

Contact Info

Product

Resources

About