Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Abstract

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Implicating the cholecystokinin B receptor in liver stem cell oncogenesis

“…6 F. The most striking finding is that many genes that were significantly upregulated by knocking out the CCK-BR were tumor suppressor genes such as Dmbt1 ( 48 ), Pcdhga12 (protocadherin gamma; 49 ), Sorcs3 (Sortilin related VPS10 domain-containing receptor 3; 50 ), and Nkx6-1 (NK6 homeobox 1; 51 ). Most of the genes downregulated when the CCK-BR was knocked out promote HCC proliferation such as Tmem45a (transmembrane protein 45a; 52 ), Spp1 (secreted phosphoprotein 1-Osteopontin; 53 ), Slco3a1 (solute carrier organic anion transporter; 54 ), and GSE1 (genetic suppressor element; 55 ). Knocking out the CCK-BR also decreased the expression of fibrosis-promoting genes including Adamts14 (codes for a disintegrin-like and metallopeptidase; 56 ) and Fst (follistatin-like 1; 57 ).…”

Blocks identical by descent in the genomes of the indigenous population of Siberia demonstrate genetic links between populations

“…Another gene, GSE1, which falls into IBD blocks in five populations, may function as an oncogene in breast, stomach, and prostate cancer, and may also be important in the treatment of patients with prostate cancer (Bamodu et al, 2021).…”

GSE1 links the HDAC1/CoREST co-repressor complex to DNA damage

“…Our identification of the GSE-HDAC1-USP22 multi-eraser complex and its function in DNA damage might be of relevance for cancer research. Various studies have recently connected GSE1 function to tumour growth in distinct types of cancer and highlighted its potential oncogenic and tumour suppressive functions (92)(93)(94)(95)(96)(97)(98). Overexpression of GSE1 was shown to promote proliferation of human breast cancer cells (93) whereas its downregulation positively correlated with decreased tumour invasion and metastasis in lung (94) or gastric cancer (98).…”