Regulation of TFEB activity and its potential as a therapeutic target against kidney diseases

Zhang, Weihuang; Li, Xiaoyü; Wang, Shujun; Chen, Yanse; Liu, Huafeng

doi:10.1038/s41420-020-0265-4

Cited by 70 publications

(59 citation statements)

References 131 publications

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“…The levels of TFEB and TFE3 are elevated in multiple types of human cancers and have been linked with both occurrence and poor prognosis 20‐22,24 . Recent study claimed that TFEB has little effect on RCC proliferation 23 .…”

Section: Resultsmentioning

confidence: 99%

“…The MiT‐TFE family of basic helix‐loop‐helix leucine‐zipper transcription factors including TFEB, TFE3, TFEC and MITF play a major role as regulators of lysosome biogenesis, cellular energy homeostasis and immune responses; thus, they were originally described as oncogenes 20 . The expression of the TFEB and TFE3 and their activity are elevated in multiple types of human cancers and associated with enhanced proliferation and motility of these cancer cells 21 . Furthermore, TFEB or TFE3 fusion and overexpression caused by chromosomal translocation events is linked with a poor prognosis in a subset of RCC patients with elevated recurrence and metastasis 22 .…”

Section: Introductionmentioning

confidence: 99%

“…20 The expression of the TFEB and TFE3 and their activity are elevated in multiple types of human cancers and associated with enhanced proliferation and motility of these cancer cells. 21 Furthermore, TFEB or TFE3 fusion and overexpression caused by chromosomal translocation events is linked with a poor prognosis in a subset of RCC patients with elevated recurrence and metastasis. 22 But the molecular mechanism is not fully understood.…”

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confidence: 99%

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TFE3‐PD‐L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

Guo

Bai

et al. 2020

J Cellular Molecular Medi

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Renal cell carcinoma (RCC) has become the most malignant tumour of kidneys in worldwide. 1 Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCCs, representing approximately 70% of all adult renal carcinomas. The other histologies mainly encompass papillary and chromophobe RCC. 2 The prognosis of ccRCC is poor: 30% of patients are metastatic at diagnosis and almost 30% of the remaining patients will develop metastasis detected during the follow-up. 3 With the continuous development of medicine, the treatment and management of ccRCC, particularly metastatic RCC, have radically changed over the past few decades. 4 Initially, first-generation immunotherapy with cytokines: interleukins or interferon represented standard approaches but with poor results. 5,6 In recent years, the development of tyrosine kinase inhibitors (TKI), mainly targeted to vascular endothelial growth factor receptor, largely improved the prognosis of both overall survival (OS) and progression free survival (PFS). 7 Sunitinib malate (Sun) is an oral multi-targeting TKI that is registered for the treatment of advanced or metastatic RCC. 8,9 Currently, the emergence of immune checkpoint inhibitors (ICI) showed promising results in RCC treatment. 10-12 Programmed cell death 1 (PD-1), programmed death ligand-1 (PD-L1)

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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TFE3‐PD‐L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

Guo

Bai

et al. 2020

J Cellular Molecular Medi

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“…Among all the four members of the MiT/TFE family, TFEB and TFE3 show a more ubiquitous pattern of expression and their functions has been widely investigated including proliferation, metabolism, and autophagy [20,24]. The tight connection of TFEB and TFE3 with renal cell carcinoma has been reported, especially in translocation renal cell carcinoma (tRCC) [21][22][23]. But its biological function is not clearly investigated.…”

Section: Discussionmentioning

confidence: 99%

“…The levels of TFEB and TFE3 are elevated in multiple types of human cancers and have been linked with both occurrence and poor prognosis [20][21][22]24]. Recent study claimed that TFEB has little effect on RCC proliferation [23].…”

Section: Tfe3 But Not Tfeb Affects Cell Proliferation Of Ccrcc Cellsmentioning

confidence: 99%

TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

Guo

Bai

et al. 2020

Preprint

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Background: The microphthalmia of bHLH-LZ transcription factors (MiT/TFE) family chromosomal translocation or overexpression is linked with a poor prognosis in clear cell renal cell carcinoma (ccRCC) with elevated recurrence and drug resistance, but the molecular mechanism is not fully understood. Here, we investigated whether the resistance to sunitinib malate (Sun), the standard treatment for metastatic RCC, is due to upregulation of programmed death ligand 1 (PD-L1) by the transcription factor E3 (TFE3) in ccRCC.Methods: The effect of TFE3 expression on ccRCC proliferation had been evaluated. The regulation of TFE3 on PD-L1 was assessed by qPCR and western blots in human primary clear cell lines and ccRCC specimens. The regulation of Sun on TFE3 and PD-L1 was assessed by western blots and flow cytometry. The therapeutic efficacy of Sun plus PD-L1 blockade was evaluated in xenograft mouse model.Results: In this study, we propose that TFE3 but not TFEB is essential for tumor survival and more importantly it is more of a promotor of cell proliferation which was associated with the poorer survival of cancer patients. We also found a positive correlation between TFE3 and PD-L1 expression in clear cell RCC cells and tissues. Sun treatment led to enhanced TFE3 nuclear translocation and PD-L1 expression. Finally, we observed the therapeutic benefit of Sun plus PD-L1 inhibition which enhanced CD8+ cytolytic activity and thus tumor suppression in a xenografted mouse model.Conclusions: Our data provides a strong rationale to apply Sun and PD-L1 inhibition jointly as a novel immunotherapeutic approach for ccRCC treatment.

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Mechanism and restoration strategy of lysosomal abnormalities induced by urinary protein overload in proximal tubule epithelial cells

Zou

Wang

et al. 2021

Developmental Dynamics

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Background: Persistent elevated concentrations of urinary protein can destroy proximal tubule epithelial cells (PTECs) by inducing lysosomal abnormalities, thereby aggravating PTEC damage and renal fibrosis. However, the specific mechanisms of these serial biochemical events and methods for treating or preventing PTEC damage upon proteinuria need further investigation. Results: In this study, electron microscopy and dual-labeled immunofluorescence analysis for identifying lysosome type revealed inadequate primary lysosome biogenesis and secondary lysosome accumulation in the PTECs of patients with minimal change nephrotic syndrome or membranous nephropathy who suffered from proteinuria. In vitro studies on HK-2 cells indicated that this abnormality was associated with decreased expression of transcription factor EB (TFEB). In contrast, TFEB overexpressing HK-2 cells under urinary protein overload exhibited significantly reduced accumulation of secondary lysosomes and increased proportion and quantity of primary lysosomes as indicated by dual-labeled immunofluorescence. Further, these cells could upregulate lysosomal degradation functions, as determined using Cathepsin L activity assays and flow cytometry for dye quenched-albumin. Conclusions: These results indicate that abnormal TFEB expression is a key mechanism of lysosomal dyshomeostasis caused by protein overload in PTECs. TFEB is thus a potential therapeutic target for the treatment of urinary protein-related kidney disease. K E Y W O R D S lysosomal dyshomeostasis, proteinuria, proximal tubule epithelial cells, transcription factor EB | INTRODUCTIONProteinuria, as a risk factor for chronic kidney disease (CKD), is an important sign of underlying renal tubular dysfunction or glomerular disease. [1][2][3] Impaired reabsorption by proximal tubules and increased permeability of the Xiaoyu Li, Ting Zou, and Shujun Wang contributed equally to this work.

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Regulation of TFEB activity and its potential as a therapeutic target against kidney diseases

Cited by 70 publications

References 131 publications

TFE3‐PD‐L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

TFE3‐PD‐L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

Mechanism and restoration strategy of lysosomal abnormalities induced by urinary protein overload in proximal tubule epithelial cells

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