DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor

Chi Hong Chao, Chun Ming Chen, Pei Lin Cheng, Jing Wen Shih, Ann Ping Tsou, Yan Hwa Wu Lee

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21 waf1/cip1, a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p21waf1/cip1 expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on p21waf1/cip1 promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the -123 to -63 region, relative to the transcription start site of p21waf1/cip1 promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21waf1/cip1. To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in ∼58% to 73% of hepatoma specimens, which led to the reduction of p21 waf1/cip1 expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in >70% of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21 waf1/cip1 promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor.

Original languageEnglish
Pages (from-to)6579-6588
Number of pages10
JournalCancer Research
Volume66
Issue number13
DOIs
Publication statusPublished - Jul 1 2006
Externally publishedYes

Fingerprint

DEAD-box RNA Helicases
Growth
Neoplasms
Transcriptional Activation
Up-Regulation
Cyclin-Dependent Kinases
Transcription Initiation Site
Gene Expression Regulation
Adenosine Triphosphatases
Hepatocellular Carcinoma
Squamous Cell Carcinoma
Cytoplasm
Down-Regulation
Messenger RNA
Skin

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor. / Chao, Chi Hong; Chen, Chun Ming; Cheng, Pei Lin; Shih, Jing Wen; Tsou, Ann Ping; Lee, Yan Hwa Wu.

In: Cancer Research, Vol. 66, No. 13, 01.07.2006, p. 6579-6588.

Research output: Contribution to journalArticle

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abstract = "DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21 waf1/cip1, a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p21waf1/cip1 expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on p21waf1/cip1 promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the -123 to -63 region, relative to the transcription start site of p21waf1/cip1 promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21waf1/cip1. To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in ∼58{\%} to 73{\%} of hepatoma specimens, which led to the reduction of p21 waf1/cip1 expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in >70{\%} of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21 waf1/cip1 promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor.",
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AU - Cheng, Pei Lin

AU - Shih, Jing Wen

AU - Tsou, Ann Ping

AU - Lee, Yan Hwa Wu

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