Abstract 1959: MTA1 promotes tumor progression and bone metastasis in prostate cancer via positive regulation of MUC1 and CTSB

Abstract

About 80% of the time that prostate cancer cells metastasize, they spread to the bones. Metastasis involves activation of invasive programs through genetic and epigenetic alterations, including changes in expression of chromatin remodeler proteins. We have previously identified metastasis-associated protein 1 (MTA1), a chromatin remodeler, as a component of vicious cycle of bone metastasis and confirmed significantly higher expression of MTA1 in bone metastatic samples from patients. In an attempt to dissect molecular mechanisms of MTA1 action, we performed integrative analysis of our bone metastasis signature data along with MTA1 ChIP-Seq data, which revealed mucin 1 (MUC1) and cathepsin B (CTSB) as strong potential candidates responsible for MTA1-driven invasiveness.Here, we show that loss of function studies with MTA1 in PC3M cells exhibit reduced expression for MUC1 and CTSB. We also demonstrate that depletion of MTA1 in PC3M aggressive prostate cancer cellsdoes not affect cell proliferation but leads to decrease in colony forming ability, invasive and migratory property of these cells. When PC3M cells silenced for MTA1 and tagged with luciferase are used to generate subcutaneous or intracardiac xenografts, it leads to reduced tumor progression or decreased metastasis to bone, respectively as evident by bioluminescent measurements and histology of tumors. Ongoing experiments aim to validate the role of MUC1 and CTSB in MTA1-driven invasiveness and metastasis in prostate cancer. Citation Format: Avinash Kumar, Swati Dhar, Gisella Campanelli, Nasir A. Butt, Christian R. Gomez, Jason M. Schallheim, Anait S. Levenson. MTA1 promotes tumor progression and bone metastasis in prostate cancer via positive regulation of MUC1 and CTSB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1959. doi:10.1158/1538-7445.AM2017-1959

Understanding and targeting anoikis in metastasis for cancer therapies

“…Furthermore, MUC1 overexpression along with MUC1 promoter methylation in the breast (Jing et al, 2019), lung (X. Huang et al, 2017), and colorectal cancer (C. Li et al, 2019) patients predicts poor prognosis. This discrepancy could be explained by the presence of overexpressed MUC1 with aberrant oncogene expressions like GATA6 inducing metastasis‐associated gene expression like β‐catenin, providing survival and metastatic advantages (Deng et al, 2020; Kumar et al, 2017). MUC1 with the potential for metastasis progression could be considered as a hallmark of resistance to anoikis (Taddei et al, 2012), leading to survival in AI condition and spreading out to the other tissues.…”

“…Huang et al, 2017), and colorectal cancer (C. Li et al, 2019) patients predicts poor prognosis. This discrepancy could be explained by the presence of overexpressed MUC1 with aberrant oncogene expressions like GATA6 inducing metastasis-associated gene expression like β-catenin, providing survival and metastatic advantages (Deng et al, 2020;Kumar et al, 2017). MUC1 with the potential for metastasis progression could be considered as a hallmark of resistance to anoikis (Taddei et al, 2012) cells prevents apoptosis by reducing ROS (Yin et al, 2007) and modulating the intrinsic apoptosis pathway (Raina et al, 2004) all could be regarded as an auxiliary power source for apoptotic response in detached cells.…”