Dataset Information

PI4KIII? is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.

ABSTRACT: Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase III? (PI4KIII?). Molecular, biochemical, and cell biological studies show that PI4KIII?-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIII?-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIII? antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIII?-dependent secretion for cancer cell survival and tumor progression.

SUBMITTER: Tan X

PROVIDER: S-EPMC7702266 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.

Tan Xiaochao X Banerjee Priyam P Pham Edward A EA Rutaganira Florentine U N FUN Basu Kaustabh K Bota-Rabassedas Neus N Guo Hou-Fu HF Grzeskowiak Caitlin L CL Liu Xin X Yu Jiang J Shi Lei L Peng David H DH Rodriguez B Leticia BL Zhang Jiaqi J Zheng Veronica V Duose Dzifa Y DY Solis Luisa M LM Mino Barbara B Raso Maria Gabriela MG Behrens Carmen C Wistuba Ignacio I II Scott Kenneth L KL Smith Mark M Nguyen Khanh K Lam Grace G Choong Ingrid I Mazumdar Abhijit A Hill Jamal L JL Gibbons Don L DL Brown Powel H PH Russell William K WK Shokat Kevan K Creighton Chad J CJ Glenn Jeffrey S JS Kurie Jonathan M JM

Science translational medicine 20200101 527

Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies ...[more]

PMID: 31969487

Similar Datasets

Project description:BackgroundHuman discs large-associated protein 5 (DLGAP5) is reported to play a pivotal role in regulating the cell cycle and implicate in tumorigenesis and progression of various cancers. Our current research endeavored to explore the prognostic value, immune implication, biological function and targeting strategy of DLGAP5 in LUAD through approaches including bioinformatics, network pharmacology analysis and experimental study.MethodsMultiple databases, including TCGA, GEO, CPTAC and Human Protein Atlas, were utilized to explore the expression and clinical significance of DLGAP5 in LUAD. The genetic alterations of DLGAP5 were assessed through cBioPortal and COSMIC databases. The relationship between DLGAP5 expression and genetic abnormalities of driver genes in LUAD was analyzed through TIMER2.0 database. CancerSEA database was utilized to explore the function of DLGAP5 in 14 different states in LUAD at single-cell resolution. GDSC database was utilized to analyze the impact of DLGAP5 on IC50 of frequently-used anti-LUAD drugs. CIBERSORT method and TIMER2.0 database was utilized to explore the relationship between DLGAP5 and tumor immune infiltration. Network pharmacology was applied to screen potential DLGAP5 inhibitor. In vitro and in vivo experiments were utilized to evaluate biological function and downstream targets of DLGAP5, and the effect of screened DLGAP5 inhibitor on LUAD growth.ResultsHigh DLGAP5 expression was commonly observed in LUAD and associated with mutation of major driver genes, poor prognosis, high IC50 values of frequently-used anti-LUAD drugs, increasing immune infiltration and elevated immune checkpoint blockade-related genes in LUAD. PLK1 was revealed as a potential DLGAP5 downstream target in LUAD. DLGAP5 overexpression or knockdown significantly promoted or inhibited LUAD cell proliferation and PLK1 expression. PLK1 overexpression well rescued DLGAP5 knockdown-induced cell proliferation inhibition, or vice versa. Furthermore, by virtual screening of an investigational drug library from the DrugBank database, AT9283 was screened and identified as a novel DLGAP5 inhibitor. AT9283 effectively suppressed growth of LUAD cells both in vitro and in vivo. DLGAP5 overexpression significantly reversed AT9283-induced proliferation inhibition. Moreover, AT9283 significantly suppressed DLGAP5 and PLK1 expression, while DLGAP5 overexpression significantly reversed AT9283-induced PLK1 suppression.ConclusionOur research has demonstrated that DLGAP5 is upregulated in LUAD and exhibits a strong correlation with unfavorable prognosis. Furthermore, DLGAP5 assumes a significant function in the regulation of tumor immunity and treatment outcome of immune checkpoint inhibitors. Of note, we found that DLGAP5 promotes cell proliferation of LUAD via upregulating PLK1. Targeting DLGAP5 by AT9283, our newly identified DLGAP5 inhibitor, suppresses LUAD growth. DLGAP5 may become a promising prognostic biomarker and therapeutic target for patients with LUAD.

Dataset Information

PI4KIII? is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.

Publications

PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets