LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

Jun Lu; Liang min Fu; Yun Cao; Yong Fang; Jia zheng Cao; Yi hui Pan; Jun jie Cen; Yan ping Liang; Zhen hua Chen; Jin huan Wei; Yong Huang; Mukhtar Adan Mumin; Quan hui Xu; Ying han Wang; Jiang quan Zhu; Hui Liang; Zhu Wang; Qiong Deng; Wei Chen; Xiao han Jin; Zhi ping Liu; Jun hang Luo

doi:10.1038/s41388-023-02666-x

LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

Jun Lu, Liang min Fu, Yun Cao, Yong Fang, Jia zheng Cao, Yi hui Pan, Jun jie Cen, Yan ping Liang, Zhen hua Chen, Jin huan Wei, Yong Huang, Mukhtar Adan Mumin, Quan hui Xu, Ying han Wang, Jiang quan Zhu, Hui Liang, Zhu Wang, Qiong Deng, Wei Chen, Xiao han JinZhi ping Liu, Jun hang Luo

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients’ tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.

Original language	English (US)
Pages (from-to)	1543-1557
Number of pages	15
Journal	Oncogene
Volume	42
Issue number	19
DOIs	https://doi.org/10.1038/s41388-023-02666-x
State	Published - May 5 2023
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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Lu, J., Fu, L. M., Cao, Y., Fang, Y., Cao, J. Z., Pan, Y. H., Cen, J. J., Liang, Y. P., Chen, Z. H., Wei, J. H., Huang, Y., Mumin, M. A., Xu, Q. H., Wang, Y. H., Zhu, J. Q., Liang, H., Wang, Z., Deng, Q., Chen, W., ... Luo, J. H. (2023). LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway. Oncogene, 42(19), 1543-1557. https://doi.org/10.1038/s41388-023-02666-x

Lu, J, Fu, LM, Cao, Y, Fang, Y, Cao, JZ, Pan, YH, Cen, JJ, Liang, YP, Chen, ZH, Wei, JH, Huang, Y, Mumin, MA, Xu, QH, Wang, YH, Zhu, JQ, Liang, H, Wang, Z, Deng, Q, Chen, W, Jin, XH, Liu, ZP & Luo, JH 2023, 'LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway', Oncogene, vol. 42, no. 19, pp. 1543-1557. https://doi.org/10.1038/s41388-023-02666-x

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title = "LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway",

abstract = "LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients{\textquoteright} tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.",

author = "Jun Lu and Fu, {Liang min} and Yun Cao and Yong Fang and Cao, {Jia zheng} and Pan, {Yi hui} and Cen, {Jun jie} and Liang, {Yan ping} and Chen, {Zhen hua} and Wei, {Jin huan} and Yong Huang and Mumin, {Mukhtar Adan} and Xu, {Quan hui} and Wang, {Ying han} and Zhu, {Jiang quan} and Hui Liang and Zhu Wang and Qiong Deng and Wei Chen and Jin, {Xiao han} and Liu, {Zhi ping} and Luo, {Jun hang}",

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year = "2023",

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doi = "10.1038/s41388-023-02666-x",

language = "English (US)",

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T1 - LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

AU - Lu, Jun

AU - Fu, Liang min

AU - Cao, Yun

AU - Fang, Yong

AU - Cao, Jia zheng

AU - Pan, Yi hui

AU - Cen, Jun jie

AU - Liang, Yan ping

AU - Chen, Zhen hua

AU - Wei, Jin huan

AU - Huang, Yong

AU - Mumin, Mukhtar Adan

AU - Xu, Quan hui

AU - Wang, Ying han

AU - Zhu, Jiang quan

AU - Liang, Hui

AU - Wang, Zhu

AU - Deng, Qiong

AU - Chen, Wei

AU - Jin, Xiao han

AU - Liu, Zhi ping

AU - Luo, Jun hang

PY - 2023/5/5

Y1 - 2023/5/5

N2 - LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients’ tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.

AB - LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients’ tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.

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LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

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