FSCN1 as a new druggable target in adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatic spread. The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with VAV2, a guanine nucleotide exchange factor for the Rho/Rac GTPase family, to enhance the invasion properties of ACC cancer cells.Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both in vitro and in an in vivo metastatic ACC zebrafish model. Here, we showed that FSCN1 is a transcriptional target for β-catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. FSCN1 knock-out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When Steroidogenic Factor-1 (SF-1) dosage was upregulated in H295R cells, activating their invasive capacities, FSCN1 knock-out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2-044, which also diminished the invasion of other ACC cell lines expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock-out cells and G2-044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 is a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC.

N6‐methyladenosine methylation on FSCN1 mediated by METTL14/IGF2BP3 contributes to human papillomavirus type 16‐infected cervical squamous cell carcinoma

“…m6A methyltransferase METTL14 can catalyse m6A methylation modification on mRNA, while reading protein IGF2BP3 can recognize the modification and affect gene expression, thereby affecting gene expression. FSCN1 is closely related to cell motility, EMT, migration, inflammation and immunity and has been reported as a potential therapeutic target for various cancers 20–23 . Interestingly, FSCN1 was predicted to have multiple m6A modification sites on its mRNA sequence through a sequence‐based m6A modification site predictor (http://www.cuilab.cn/sramp/).…”

“…To validate the influence of HPV16 on the expression of these two inflammation and immunity and has been reported as a potential therapeutic target for various cancers. [20][21][22][23] Interestingly, FSCN1 was predicted to have multiple m6A modification sites on its mRNA sequence through a sequence-based m6A modification site predictor (http:// www.cuilab.cn/sramp/). Using MeRIP-PCR analysis, we found that overexpressing HPV16 E6/E7 increased m6A modification and expression of FSCN1.…”

Roles and mechanisms of circular RNA in respiratory system cancers

“…This elevation of FOXM1 subsequently enhanced the expression of downstream cell cycle-related genes CENPA and CENPB, driving cell cycle progression and cell proliferation. Moreover, Facin Actin-bundling Protein 1 (FSCN1) is an important protein that regulates cancer cell migration and invasion ( 91 ). Zhang et al.…”

A reappraisal of transcriptional regulation by NR5A1 and beta-catenin in adrenocortical carcinoma

“…We have demonstrated that NR5A1 overexpression in ACC cells regulates the expression of both positive and negative dosage-dependent target genes which are directly implicated in shaping the malignant tumour phenotype (3)(4)(5)(6)(7)(8). On the other hand, activating mutations in CTNNB1 and other genetic alterations in canonical Wnt pathway components in ACC induce nuclear translocation of beta-catenin and transcriptional regulation of genes involved in cell proliferation, apoptosis and invasion, being also associated to immune cell exclusion from the tumour (16,(26)(27)(28)(29)(30)(31). Overall, these data suggest a model where NR5A1 overexpression and beta-catenin activation principally act in parallel, rather than functionally interacting, to drive ACC malignancy (Figure 3).…”