Function of phosphorylation of NF-kB p65 ser536 in prostate cancer oncogenesis

Oncotarget
Li ZhangJianghua Wang

Abstract

Majority of prostate cancer (PCa) patients carry TMPRSS2/ERG (T/E) fusion genes and there has been tremendous interest in understanding how the T/E fusion may promote progression of PCa. We showed that T/E fusion can activate NF-kB pathway by increasing phosphorylation of NF-kB p65 Ser536 (p536), but the function of p536 has never been studied in PCa. We report here that active p536 can significantly increase cell motility and transform PNT1a cells (an immortalized normal cell line), suggesting p536 plays a critical role in promoting PCa tumorigenesis. We have discovered a set of p536 regulated genes, among which we validated the regulation of CCL2 by p536. Based on all evidence, we favor that T/E fusion, NF-kB p536 and CCL2 form a signaling chain. Finally, PNT1a cells (not tumorigenic) can form tumors in SCID mice when overexpressing of either wild type or active p65 in the presence of activated AKT, demonstrating synergistic activities of NF-kB and AKT signals in promoting PCa tumorigenesis. These findings indicate that combination therapies targeting T/E fusion, NF-kB, CCL2 and/or AKT pathways may have efficacy in T/E fusion gene expressing PCa. If successful, such targeted therapy will benefit more than half of PCa patients...Continue Reading

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Citations

Sep 5, 2019·Journal of Experimental & Clinical Cancer Research : CR·Yong WangDan Yue
Sep 13, 2019·Critical Reviews in Food Science and Nutrition·Haroon KhanHui Cao
Sep 16, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Oriana Lo ReManlio Vinciguerra
Dec 8, 2016·Journal of Cellular Physiology·Maria M BarrecaFabiana Geraci
Aug 4, 2020·PLoS Computational Biology·Giorgos MinasDavid A Rand
Jun 9, 2020·Acta Biochimica Et Biophysica Sinica·Zhongquan ZhouWanqing Shi
Jun 28, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ninghong JiangLong Sui
Oct 4, 2017·APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica·Kah Keng WongJosé I López
Nov 3, 2016·Cancer Research·Li ZhangMichael Ittmann
Oct 2, 2019·Cell Cycle·Shasha HouXiaxia Yuan
Aug 30, 2021·The Prostate·Longjiang ShaoMichael Ittmann
Sep 26, 2021·Journal of Experimental & Clinical Cancer Research : CR·Yang WangQing-Yu He

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Datasets Mentioned

BETA
GSE63210

Methods Mentioned

BETA
ubiquitination
PCR
xenograft
chip
Feature Extraction
ELISA
transfection
Assay

Software Mentioned

InForm
Feature Extraction
Java TreeView
BioConductor

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