AZGP1P2/UBA1/RBM15 Cascade Mediates the Fate Determinations of Prostate Cancer Stem Cells and Promotes Therapeutic Effect of Docetaxel in Castration-Resistant Prostate Cancer via TPM1 m6A Modification

Abstract

Prostate cancer (PCa) is a common malignant tumor with high morbidity and mortality worldwide. The prostate cancer stem cell (PCSC) model provides novel insights into the pathogenesis of PCa and its therapeutic response. However, the roles and molecular mechanisms of specific genes in mediating fate decisions of PCSCs and carcinogenesis of PCa remain to be elusive. In this study, we have explored the expression, function, and mechanism of AZGP1P2, a pseudogene of AZGP1, in regulating the stemness and apoptosis of PCSCs and treatment resistance of docetaxel in castration-resistant prostate cancer (CRPC). We revealed that AZGP1P2 was downregulated in CRPC cell lines and PCSCs, while it was positively associated with progression-free interval. Upregulation of the AZGP1P2 enhanced the sensitivity of docetaxel treatment in CRPCs via inhibiting their stemness. RNA pull-down associated with mass spectrometry analysis, co-immunoprecipitation assay, and RNA immunoprecipitation assay demonstrated that AZGP1P2 could bind to UBA1 and RBM15 as a “writer” of methyltransferase to form a compound. UBA1, an E1 ubiquitin-activating enzyme, contributed to RBM15 protein degradation via ubiquitination modification. Methylated RNA immunoprecipitation assay displayed that RBM15 controlled the mRNA decay of TPM1 in m6A methylation. Furthermore, a xenograft mouse model and patient-derived organoids showed that the therapeutic effect of docetaxel in CRPC was increased by AZGP1P2 in vivo. Collectively, these results imply that AZGP1P2 mediates the stemness and apoptosis of PCSCs and promotes docetaxel therapeutic effect by suppressing tumor growth and metastasis via UBA1/RBM15-mediated TPM1 mRNA decay in CRPC.

Comparative Genome-Wide Alternative Splicing Analysis between Preadipocytes and Adipocytes

“…Tropomyosin 1 (TPM1) plays an important role in lung cancer, colorectal cancer, and gastric cancer [28,29]. Recently, it has been found that m6A modification of TPM1 can promote the therapeutic efficacy of prostate cancer by mediating m6A modification [30], which affects the expression level of mRNA by affecting its shearing and translation [31]. Whether the differential shearing of TPM1 is regulated by m6A modification needs to be further verified.…”

CD133 significance in glioblastoma development: in silico and in vitro study

“…It has been shown that cancer stem cells can be responsible for the source of factors associated with poor survival of cancer patients [ 28 ]. CD133 has been reported as a cancer stem cell marker in various malignancies [ 5 , 29 , 30 ]. CD133 is located on chromosome 4p15.33; this glycoprotein is on the cell membrane [ 31 ].…”

PPARG is a potential target of Tanshinone IIA in prostate cancer treatment: a combination study of molecular docking and dynamic simulation based on transcriptomic bioinformatics

“…Tanshinone IIA is a crucial natural product, and gaining insight into its mechanism of action is pivotal in facilitating further research and its potential application in the development of effective treatments for prostate cancer. However, based on previous research, prostate cancer can develop resistance to small molecule drugs through various mechanisms, such as the secretion of IGF-1 by adipocytes and the regulation of m6a methylation levels [ 49 , 50 ]. As a small molecule drug, the potential resistance of prostate cancer to Tanshinone IIA should be a subject of concern in future research.…”