Targeting SALL4 by entinostat in lung cancer

Abstract

The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling of SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Connectivity Map analysis revealed the HDAC inhibitor entinostat as a potential drug in treating SALL4-expressing cancers, and this was confirmed in 17 lung cancer cell lines. In summary, we report for the first time that entinostat can target SALL4-positive lung cancer. This lays the foundation for future clinical studies evaluating the therapeutic efficacy of entinostat in SALL4-positive lung cancer patients.

SALL4 promotes the tumorigenicity of cervical cancer cells through activation of the Wnt/β‐catenin pathway via CTNNB1

“…SALL4B, but not SALL4A, can maintain the pluripotent state of mouse embryonic stem cells . High expression of SALL4 has been observed in several tumors including liver cancer, lung cancer, acute/chronic myeloid leukemia, gastric cancer, prostate cancer, colorectal cancer, breast cancer, and endometrial cancer . SALL4 acts as a novel oncogene that plays an important role in the initiation and progression of tumors.…”

New High-Throughput Screening Identifies Compounds That Reduce Viability Specifically in Liver Cancer Cells That Express High Levels of SALL4 by Inhibiting Oxidative Phosphorylation

“…A confounding issue is that SALL4A and SALL4B are coexpressed from the same gene locus as splice isoforms 15 and, from prior work, are always coexpressed in the same cell line or tumor tissue. 14,20,27 Our study shows that both SALL4 isoforms can functionally upregulate, and thus create a dependency on, oxidative phosphorylation. Targeting this pathway shared by both isoforms with oxidative phosphorylation inhibitors is therefore a viable therapeutic option for SALL4-expressing cancers.…”

“…This panel includes 2 patientderived primary cell lines, HCC9.2 and HCC26.1, from 2 Singapore patients with HCC and an immortalized normal liver cell line THLE-3 ( Figure 3A and Supplementary Figure 3A). We also tested oligomycin A in a pair of nonsmall-cell lung cancer (NSCLC) cell lines, in which the SALL4 hi H661 line was previously shown to be dependent on SALL4 expression, whereas the SALL4 lo H1299 line was not 27 (Supplementary Figure 3B and C and Supplementary Table 1B). Our data suggest that oligomycin A is potent and selective against SALL4 hi expressing HCC and NSCLC cell lines ( Figure 3A, Supplementary Figure 3A-C, and Supplementary Tables 1A and B).…”

An integrated analysis of mRNA-miRNA transcriptome data revealed hub regulatory networks in three genitourinary cancers

“…We selected four genes affecting survivorship curve, which were also in the hub interaction network analyzed in three cancers: TTN (up-regulated network in ccRCC), CDC42(upregulated network in TCC), RHEB (down-regulated network in TCC) and SALL4(up-regulated network in TGCT). SALL4 (Sal-like protein 4) is recognized as a potential biomarker for assessing cancer prognosis, higher expression of SALL4 predicts poor cancer prognosis in various cancers including gastric cancer, lung cancer, breast cancer and prostate cancer (Dirican et al, 2016;Lai et al, 2016;Yong et al, 2016;Yuan et al, 2016;Shen et al, 2017). The small GTPase RHEB promotes cancer cell survival throughp27Kip1dependent activation of autophagy (Campos et al, 2016), and it also functions in liver cancer, colon cancer cells, bladder cancer and prostate cancer (Kobayashi et al, 2010;Campos et al, 2013;Tigli et al, 2013;Zheng et al, 2015).…”