FAM64A Potentiates Bladder Carcinoma Tumorigenesis and Metastasis Through PI3K/mTORC2/AKT Pathway Activation

TL;DR

This study shows that FAM64A promotes bladder cancer growth and spread by activating a key signaling pathway, and blocking this pathway with Taselisib can reverse these effects.

Contribution

The study identifies FAM64A as a novel driver of bladder cancer progression through the PI3K/mTORC2/AKT pathway.

Findings

FAM64A is upregulated in bladder cancer and linked to advanced tumor stages.

FAM64A promotes cell cycle progression and EMT via the PI3K/mTORC2/AKT pathway.

Taselisib, a PI3K inhibitor, reverses FAM64A-induced malignant effects.

Abstract

This study establishes FAM64A as a critical driver of bladder cancer progression. We demonstrate that FAM64A accelerates cell cycle progression and induces epithelial–mesenchymal transition (EMT) through activation of the PI3K/mTORC2/AKT signaling pathway, thereby promoting tumor growth and metastasis. The PI3K inhibitor Taselisib effectively reverses these malignant phenotypes induced by FAM64A. These findings nominate FAM64A as both a prognostic biomarker and a promising therapeutic target in bladder cancer.

Background: FAM64A is highly expressed in various cancers (e.g., breast cancer, ovarian cancer), indicating that it promotes tumorigenesis and progression by facilitating epithelial–mesenchymal transition. In the genitourinary system, dihydrotestosterone promotes the expression of FAM64A by binding of the androgen receptor to the FAM64A promoter, thereby enhancing the proliferation, migration, and cell cycle progression of androgen-dependent prostate cancer cell lines. However, its specific role in the initiation and progression of bladder cancer remains unclear. FAM64A overexpression has been observed in cancers such as breast and prostate; however, its role in bladder cancer (BLCA) is less understood. Muscle-invasive BLCA (MIBC) has a poor prognosis, with five-year survival rates below 50%. This study explores FAM64A’s molecular mechanisms and therapeutic potential in BLCA. Methods: FAM64A expression was analyzed using TCGA data and clinical BLCA tissues. Functional assays (CCK-8, wound-healing, Transwell) assessed proliferation, migration, and invasion following FAM64A modulation. Western blotting was used to evaluate EMT markers (Vimentin, Slug) and proteins involved in the PI3K/AKT pathway. Bioinformatics (TCGA/GTEx) identified FAM64A-correlated genes, followed by KEGG pathway analysis. Taselisib (PI3K/AKT inhibitor) validated pathway involvement. Results: FAM64A was upregulated in BLCA and correlated with advanced tumor stage, T-stage, and grade. Knockdown suppressed proliferation, migration, and invasion, while overexpression exacerbated these effects. FAM64A promoted G2/M progression (via Cyclin B1/Ki67) and EMT (via Vimentin/Slug). KEGG analysis linked FAM64A to the PI3K/mTORC2/AKT signaling pathway. Taselisib reversed FAM64A-induced EMT and malignant phenotypes. Conclusions: FAM64A drives BLCA progression via PI3K/mTORC2/AKT-mediated EMT, serving as a potential prognostic biomarker and therapeutic target for metastatic BLCA.

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