TFEB Promotes Prostate Cancer Progression via Regulating ABCA2-Dependent Lysosomal Biogenesis

Abstract

Transcription factor EB (TFEB), a member of the MiT family, is dysregulated in different cancers and exerts specific biological functions within the tumor microenvironment. Downregulation of TFEB induces macrophage polarization in the TME and promotes tumor progression. However, the biological role and clinical significance of TFEB in prostate cancer (PCa) remain unknown. This study aimed to identify the role of TFEB in PCa and its potential clinical value. We explored TFEB expression in PCa using public databases and verified its prognostic value using immunohistochemistry in PCa tissue samples. The results revealed that TFEB expression was up-regulated in PCa tissues and was associated with cancer metastasis. Next, overexpression of TFEB promoted PCa cell malignant behavior in in vivo and in vitro experiments. RNA-sequencing and bioinformatics analysis showed high expression of TFEB promoted lysosomal biogenesis and knockdown of TFEB expression decreased the number of lysosomes. Furthermore, the ATP-binding cassette transporter A2 (ABCA2) was identified as a target gene of TFEB, which was verified using the cleavage under targets and release using nuclease (CUT&RUN) assay and qRT-PCR. Silencing of ABCA2 reduced lysosomal biogenesis and decreased matrix metalloproteinases expression, which reduced PCa cell invasion and migration in the tumor microenvironment. Our study suggests that TFEB promotes PCa progression by regulating ABCA2 through lysosomal biogenesis and may serve as a prognostic factor or as a potential therapeutic target of PCa.

WITHDRAWN: Identification of Lysosome-related Biomarkers for Predicting Prognosis and Immunotherapeutic Response in Breast Cancer

“…Accumulating studies suggest that lysosomes are involved in tumorigenesis, drug resistance, and cancer therapy for various cancers, including prostate cancer [39], lung cancer [40], and BRCA [41]. Lysosomes manipulate growth factor signaling and provide nutrition in BRCA, therefore play a crucial role [42,43].…”

Therapeutic advantage of targeting lysosomal membrane integrity supported by lysophagy in malignant glioma

“…The inhibitory effects of CQ and ifenprodil on spheroid formation were remarkable in GBM cells but not in nontransformed neural progenitor cells. These findings indicate that lysosomal activity or functions may be different between normal and malignant cells, and that cancer development and its malignant progression may be highly dependent on lysosomal activity 21 . For example, lysosomal activity is required to acquire energy essential for cancer cell proliferation 22 .…”

“…These findings indicate that lysosomal activity or functions may be different between normal and malignant cells, and that cancer development and its malignant progression may be highly dependent on lysosomal activity. 21 For example, lysosomal activity is required to acquire energy essential for cancer cell proliferation. 22 Uptake of extracellular materials mediated by phagocytosis, endocytosis, and micropinocytosis is needed to supply carbohydrates, lipids, and amino acids, which support cancer cell proliferation.…”

EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvation

“…However, transcriptional regulation represents an additional important layer to control TFEB activity, with significant implications for cellular metabolism. Indeed, multiple studies correlate increased levels of TFEB with poor prognosis in several types of cancers, including glioblastoma [37], non-small lung cancer [38], breast carcinoma [39], and prostate cancer [40]. Recently, we demonstrated that sustained activation of TFEB is the main driver of renal tumorigenesis in a mouse model of BHD syndrome, which is caused by FLCN mutations, prompting research into strategies to counteract TFEB activation [9].…”