DataSheet_1_TFEB Promotes Prostate Cancer Progression via Regulating ABCA2-Dependent Lysosomal Biogenesis.pdf

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.

转录因子EB（Transcription factor EB, TFEB）作为MiT家族成员，在多种癌症中存在表达失调现象，并在肿瘤微环境（tumor microenvironment, TME）中发挥特定生物学功能。TFEB的下调可诱导肿瘤微环境中的巨噬细胞极化，进而促进肿瘤进展。然而，TFEB在前列腺癌（prostate cancer, PCa）中的生物学作用与临床意义仍未明确。本研究旨在明确TFEB在前列腺癌中的作用及其潜在临床价值。我们通过公共数据库探究了TFEB在前列腺癌中的表达情况，并利用免疫组化（immunohistochemistry）技术在前列腺癌组织样本中验证了其预后价值。结果显示，TFEB在前列腺癌组织中表达上调，且与肿瘤转移密切相关。随后，体内与体外实验均证实，TFEB过表达可增强前列腺癌细胞的恶性表型。RNA测序（RNA-sequencing）与生物信息学分析表明，TFEB高表达可促进溶酶体生物发生，而敲低TFEB的表达则会减少溶酶体的数量。此外，本研究鉴定出ATP结合盒转运蛋白A2（ATP-binding cassette transporter A2, ABCA2）为TFEB的靶基因，并通过靶基因切割与释放核酸酶（cleavage under targets and release using nuclease, CUT&RUN）实验与qRT-PCR验证了这一结果。敲低ABCA2可抑制溶酶体生物发生并降低基质金属蛋白酶（matrix metalloproteinases）的表达水平，从而削弱前列腺癌细胞在肿瘤微环境中的侵袭与迁移能力。本研究表明，TFEB可通过溶酶体生物发生调控ABCA2进而促进前列腺癌进展，有望成为前列腺癌的预后标志物或潜在治疗靶点。