Chromodomain Helicase/ATPase DNA-Binding Protein 1-Like Gene (CHD1L) Expression and Implications for Invasion and Metastasis of Breast Cancer

Abstract

BackgroundChromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L), also known as ALC1 (amplified in liver cancer 1 gene), is a new oncogene amplified in many solid tumors. Whether this gene plays a role in invasion and metastasis of breast cancer is unknown.MethodsImmunohistochemistry was performed to detect the expression of CHD1L in patients with invasive ductal carcinoma and normal mammary glands. Chemotaxis, wound healing, and Transwell invasion assays were also performed to examine cell migration and invasion. Western blot analysis was conducted to detect the expression of CHD1L, MMP-2, MMP-9, pAkt/Akt, pARK5/ARK5, and pmTOR/mTOR. Moreover, ELISA was carried out to detect the expression levels of MMP-2 and MMP-9. Nude mice xenograft model was used to detect the invasion and metastasis of breast cancer cell lines.ResultsCHD1L overexpression was observed in 112 of 268 patients (41.8%). This overexpression was associated with lymph node metastasis (P = 0.008), tumor differentiation (P = 0.020), distant metastasis (P = 0.026), MMP-2 (P = 0.035), and MMP-9 expression (P = 0.022). In the cell experiment, reduction of CHD1L inhibited the invasion and metastasis of breast cancer cells by mediating MMP-2 and MMP-9 expression. CHD1L knockdown via siRNA suppressed EGF-induced pAkt, pARK5, and pmTOR. This knockdown inhibited the metastasis of breast cancer cells into the lungs of SCID mice.ConclusionsCHD1L promoted the invasion and metastasis of breast cancer cells via the PI3K/Akt/ARK5/mTOR/MMP signaling pathway. This study identified CHD1L as a potential anti-metastasis target for therapeutic intervention in breast cancer.

Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1

“…Human ALC1 (Amplified in liver cancer 1), also known as CHD1L (Chromodomain-helicase-DNA-binding protein 1-like), is a remodeler encoded by a gene located within human chromosome 1q21, a region that is frequently amplified in hepatocellular carcinomas ( Ma et al., 2008 , Marchio et al., 1997 , Wong et al., 2003 ). Evidence suggests that ALC1 is a driver of oncogenesis ( Chen et al., 2009 , Chen et al., 2010 , Ma et al., 2008 , Mu et al., 2015 ). Additionally, ALC1 is involved in DNA damage repair ( Ahel et al., 2009 , Gottschalk et al., 2009 , Gottschalk et al., 2012 , Pines et al., 2012 , Sellou et al., 2016 ).…”

Chromatin remodeler ALC1 prevents replication-fork collapse by slowing fork progression

“…The ALC1 gene is frequently amplified and overexpressed in human hepatocellular carcinoma and numerous solid tumors. This overexpression is associated with lymph-node metastasis, tumor differentiation, and distant metastasis [ 42 , 43 ], suggesting that the ALC1 gene plays a role in invasion and metastasis of cancer cells. In contrast to the hypoxic microenvironment of solid tumors, malignant cells are exposed to a high concentration of oxygen during hematogenous metastasis.…”

Prognostic role of chromodomain helicase DNA binding protein 1-like protein in human solid cancers

“…[ 20 ] And in PC, CHD1L-Wnt/β-catenin was showed to be a novel pathway involved in PC progression. [ 11 ] Another study by Mu et al [ 14 ] showed that CHD1L could promote the invasion and metastasis of BC cells via the PI3K/Akt/ARK5/mTOR/MMP signaling pathway in BC. Furthermore, CHD1L was also involved in the progression of glioma, Sun et al [ 13 ] reported that suppression of CHD1L could induce cell cycle arrest and increase apoptosis in glioma cells, and the knockdown of CHD1L could significantly accelerate migration and invasion ability.…”