Identification of sequence-specific interactions of the CD44-intracellular domain with RUNX2 in the transcription of matrix metalloprotease-9 in human prostate cancer cells.

Linda T Senbanjo,Mohammed Alqranei,Hanan Aljohani,Meenakshi A Chellaiah,Tao Ma,Sunipa Majumdar

doi:10.20517/cdr.2020.21

Linda T Senbanjo, Mohammed Alqranei + Show 4 more

Open Access

https://doi.org/10.20517/cdr.2020.21

Copy DOI

Journal: Cancer drug resistance	Publication Date: Jan 1, 2020
Citations: 6	License type: cc-by

Affiliation: University of Maryland, Baltimore

Abstract

Aim: The Cluster of differentiation 44 (CD44) transmembrane protein is cleaved by γ-secretase, the inhibition of which blocks CD44 cleavage. This study aimed to determine the biological consequence of CD44 cleavage and its potential interaction with Runt-related transcription factor (RUNX2) in a sequence-specific manner in PC3 prostate cancer cells.Methods: Using full-length and C-terminal deletion constructs of CD44-ICD (D1-D5) expressed as stable green fluorescent protein-fusion proteins in PC3 cells, we located possible RUNX2-binding sequences.Results: Chromatin immunoprecipitation assays demonstrated that the C-terminal amino acid residues between amino acids 671 and 706 in D1 to D3 constructs were indispensable for sequence-specific binding of RUNX2. This binding was minimal for sequences in the D4 and D5 constructs. Correspondingly, an increase in matrix metalloprotease-9 (MMP-9) expression was observed at the mRNA and protein levels in PC3 cells stably expressing D1–D3 constructs.Conclusion: These results provide biochemical evidence for the possible sequence-specific CD44-ICD/RUNX2 interaction and its functional relationship to MMP-9 transcription in the promoter region.

Highlights

After lung cancer, prostate cancer is the second leading cause of death in men . [1,2] treatment options for early-stage prostate cancer are beneficial, metastatic prostate cancer treatment options are more challenging[3]
This study aimed to identify the ability of the Cluster of differentiation 44 (CD44)-ICD sequence to activate the transcription of a metastatic protein of interest through its interaction with RUNX2, which would provide a mechanism for increasing its different functional potential
Prostate cancer PC3 cells highly express CD44, CD44-ICD, and RUNX2 proteins, which colocalize in the nucleus

Summary

Introduction

Prostate cancer is the second leading cause of death in men . [1,2] treatment options for early-stage prostate cancer are beneficial, metastatic prostate cancer treatment options are more challenging[3]. Metastases of prostate cancer to distant sites, including bone, liver, lungs, lymph nodes, and adrenals, are often difficult to treat[4]. The primary treatment option for men with advanced-stage prostate cancer is androgen deprivation therapy (ADT). Cluster of differentiation 44 (CD44) is a multifunctional cell surface receptor that has been shown to increase the metastatic potential of various types of cancer cells, including prostate cancer cells[6,7,8,9,10]. CD44 interactions with various ligands including hyaluronic acid, osteopontin (OPN), matrix metalloproteinases (MMPs), and collagens[11,12,13] play a crucial role in cancer cell migration and invasion. The CD44osteopontin interaction regulates cell migration to and invasion at distant sites[12]. The interaction of CD44 with the proteolytic form of MMP-9 is involved in the invasion of PC3 cells[6]

Objectives

Methods

Results

Conclusion