A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients

Abstract

Rationale: Effective targeting therapies are limited in Hepatocellular carcinoma (HCC) clinic. Characterization of tumor suppressor genes (TSGs) and elucidation their signaling cascades could shed light on new strategies for developing targeting therapies for HCC.Methods: We checked genome-wide DNA copy number variation (CNV) of HCC samples, focusing on deleted genes for TSG candidates. Clinical data, in vitro and in vivo data were collected to validate the tumor suppressor functions.Results: Focal deletion of GATA4 gene locus was the most prominent feature across all liver cancer samples. Ectopic expression of GATA4 resulted in senescence of HCC cell lines. Mechanistically, GATA4 exerted tumor suppressive role by orchestrating the assembly of a tumor suppressor enhancing module: GATA4 directly bound and potently inhibited the mRNA transcription activity of β-catenin; meanwhile, β-catenin was recruited by GATA4 to promoter regions and facilitated transcription of GATA4 target genes, which were TSGs per se. Expression of GATA4 was effective to shrink GATA4-deficient HCC tumors in vivo. We also showed that β-catenin inhibitor was capable of shrinking GATA4-deficient tumors.Conclusions: Our study unveiled a previously unnoticed tumor suppressor enhancing module assembled by ectopically expressed GATA4 in HCC cells and denoted a therapeutic opportunity for GATA4 deficient HCC patients. Our study also presented an interesting case that an oncogenic transcription factor conditionally functioned as a tumor suppressor when recruited by a TSG transcription factor.

RETRACTED: A Novel Tumor Suppressor Gene, ZNF24, Inhibits the Development of NSCLC by Inhibiting the WNT Signaling Pathway to Induce Cell Senescence

“…Furthermore, the Western results confirmed that ZNF24 expression reduced the protein levels of c-MYC, cJUN, and fra-1 (Figure 4F and Supplement Figure S1D). Previous studies by Lu et al have shown that the WNT signaling pathway is associated with tumor cell senescence (27). This was consistent with our b-galactosidase staining results that ZNF24 induced A549i and PC9i cell senescence (Figure 4G and Supplement Figure S1E).…”

The Novel Tumor Suppressor Gene ZNF24 Induces THCA Cells Senescence by Regulating Wnt Signaling Pathway, Resulting in Inhibition of THCA Tumorigenesis and Invasion

“…In order to find out the precise mechanisms related to the ZNF24induced aging of THCA cells.Lu et al reported that Wnt signaling pathway is related to tumor cells senescence (11). We dected the impact of ZNF24 on Wnt signaling pathway in BCPAPi cells, and the qPCR assay result showed that ZNF24 expression significantly downregulated target genes in the typical Wnt signal transduction pathway, such as CCND2, cJUN, C-MYC and AXIN2 (Figure 4A).…”

“…This indicates that CTNNB1 may be closely related to the tumorigenesis of THCA. In addition, Lu et al have reported that GATA4 directly binds and inhibits the bcatenin activity in transcribing target genes involved in the classical Wnt pathway, which result in Hepatocellular carcinoma (HCC) cells senescence (11). We therefore hypothesize that b-catenin might also be related to THCA tumor cell senescence.…”

Potential Prognostic Immune Biomarkers of Overall Survival in Ovarian Cancer Through Comprehensive Bioinformatics Analysis: A Novel Artificial Intelligence Survival Prediction System

“…MYH11 positively regulated GSTM5, PTGIS, ENPP2, and P4HA3 ( 32 ). GATA4 inhibits tumour growth by affecting the assembly of tumour suppressor enhancement modules ( 33 ). Overexpression of GATA4 can protect human granulosa cell tumours from apoptosis induced by TRAIL in vitro ( 34 ).…”