Evidence map›Paper›PMID 26640144›Full record

ArticleOncogene2016

HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer.

M Ruscetti, E L Dadashian, W Guo, B Quach, D J Mulholland, J W Park, L M Tran, N Kobayashi, D Bianchi-Frias, Y Xing and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncogene, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
95citing papers in PubMed, 1 pooled it
7.4field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

95 citing papers in PubMed, 1 synthesis or guideline pooled it, 144 citations in OpenAlex.

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35 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 3 institutions in 2 countries.

M RuscettiMolecular Biology Institute, UCLA, Los Angeles, CA, USA.
E L DadashianDepartment of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
W GuoSchool of Life Sciences, Peking University, Beijing, China.
B QuachDepartment of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
D J MulhollandDepartment of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
J W ParkDepartment of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA.
L M TranDepartment of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
N KobayashiDepartment of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
D Bianchi-FriasDivisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Y XingDepartment of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA.
P S NelsonDivisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
H WuMolecular Biology Institute, UCLA, Los Angeles, CA, USA.
Fred Hutch Cancer Center · USPeking University · CNUniversity of California, Los Angeles · US

Funding

TRANSCRIPTOME AND PROTEOME STRATIFICATION OF PROSTATE ADENOCARCINOMA PHENOTYPESP50CA097186 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI John Kyung Lee · 2002 to 2026
$58.1M
UCLA SPORE IN PROSTATE CANCERP50CA092131 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI FREEMAN, MICHAEL R · 2002 to 2023
$42.6M
Steroid Metabolism in Castration-Resistant Prostate CancerP01CA163227 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI Henry W. Long · 2013 to 2026
$25.0M
TUMOR CELL SURFACES AND CHROMOSOMEST32CA009056 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Gay M Crooks, David A. Nathanson · 1985 to 2026
$10.5M
Influences of the Microenvironment on Cancer Stem CellsU01CA164188 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI NELSON, PETER S, WITTE, OWEN N. · 2011 to 2015
$2.9M
Chronic inhibition of androgen receptor signaling leads to neuroendocrine prostate cancer by trans differentiation of stem/progenitor cellsR01CA197910 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI MULHOLLAND, DAVID · 2015 to 2019
$2.0M
Study of cell-of-origin and cancer stem cells in prostatic adenocarcinomaR01CA121110 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI WU, HONG · 2008 to 2012
$1.7M
PTEN and Prostate Cancer ProgressionR01CA107166 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI WU, HONG · 2004 to 2008
$1.7M
Deciphering Beta-Catenin Contributions in Prostate CanceF32CA112988 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MULHOLLAND, DAVID · 2005 to 2008
$138k
NCI NIH HHS F32 CA112988NCI NIH HHS P01 CA163227NCI NIH HHS P50 CA092131NCI NIH HHS P50 CA097186NCI NIH HHS R01 CA107166NCI NIH HHS R01 CA121110NCI NIH HHS R01 CA197910NCI NIH HHS T32 CA009056NCI NIH HHS U01 CA164188
6 · The paper itself

Abstract

PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial-mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial-mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial-mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589.

Indexed as

AnimalsBlotting, WesternCell Line, TumorDisease Models, AnimalEpithelial-Mesenchymal TransitionGene Expression ProfilingGene Expression Regulation, NeoplasticHistone Deacetylase InhibitorsHumansHydroxamic AcidsIndolesMaleMice, Inbred NODMice, KnockoutMice, SCIDMice, TransgenicHistone Deacetylase InhibitorsHras protein, mouseHydroxamic AcidsIndolesMitogen-Activated Protein KinasesPanobinostatPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktProto-Oncogene Proteins p21(ras)PTEN PhosphohydrolasePten protein, mouse

Identifiers

PMID26640144
PMCPMC4896852
OpenAlexW2192807450

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.