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RB1CC1 functions as a tumor-suppressing gene in renal cell carcinoma via suppression of PYK2 activity and disruption of TAZ-mediated PDL1 transcription activation

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Abstract

Rb1-inducible coiled-coil 1 (RB1CC1) has been demonstrated to function as an inhibitor of proline-rich/Ca-activated tyrosine kinase 2 (PYK2) by binding to the kinase domain of PYK2, which promotes the proliferation, invasion, and migration of renal cell carcinoma (RCC) cells. Additionally, in breast cancer, PYK2 positively regulates the expression of transcriptional co-activator with PDZ-binding motif (TAZ) which in turn can enhance PDL1 levels in breast and lung cancer cells. The current study was performed to decipher the impact of RB1CC1 in the progression of RCC via regulation of the PYK2/TAZ/PDL1 signaling axis. Expression of RB1CC1 and PYK2 was quantified in clinical tissue samples from RCC patients. The relationship between TAZ and PYK2, TAZ and PDL1 was then validated. The cellular processes of doxorubicin (DOX)-induced human RCC cell lines including the abilities of proliferation, colony formation, sphere formation and apoptosis, as well as the tumorigenicity of transfected cells, were evaluated after the alteration of RB1CC1 expression. RB1CC1 exhibited decreased expression in RCC tissues and was positively correlated with patient survival. RB1CC1 could inhibit the activity of PYK2, which in turn stimulated the stability of TAZ protein by phosphorylating TAZ. Meanwhile, TAZ protein activated PDL1 transcription by binding to the promoter region of PDL1. RB1CC1 overexpression or PYK2 knockdown could help everolimus (EVE) to inhibit tumor proliferation and activate immune response. Taken together, RB1CC1 can potentially augment the response of RCC cells to immunotherapy by suppressing the PYK2/TAZ/PDL1 signaling axis.

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Data availability and materials

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ANOVA:

Analysis of variance

ATCC:

American Type Culture Collection

BCA:

Bicinchoninic acid

BFGF:

Basic fibroblast growth factor

BSA:

Bovine serum albumin

CCK-8:

Cell counting kit-8

CDNA:

Complementary DNA

ChIP:

Chromatin immunoprecipitation

Co-IP:

Co-immunoprecipitation

DAB:

Diaminobenzidine

DAPI:

4′,6-Diamidino-2-phenylindole

DMEM:

Dulbecco's modified Eagle’s medium

DOX:

Doxorubicin

ECL:

Enhanced chemiluminescence

EDTA:

Ethylenediamine tetraacetic acid

EGF:

Endothelial growth factor

EVE:

Everolimus

FAK:

Focal adhesion kinase

FBS:

Fetal bovine serum

FIP200:

Family interacting protein of 200 kD

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GDNA:

Genomic DNA

GEO:

Gene Expression Omnibus

HER2:

Human epidermal growth factor receptor 2

IgG:

Immunoglobulin G

KIRC:

Kidney renal clear cell carcinoma

KIRP:

Kidney renal papillary cell carcinoma

NC:

Negative control

OD:

Optical density

PDL1:

Programmed cell death ligand 1

PSCA:

Prostate stem cell antigen

PVDF:

Polyvinylidene fluoride

PYK2:

Proline-rich/Ca-activated tyrosine kinase 2

RB1CC1:

Rb1-inducible coiled-coil 1

RCC:

Renal cell carcinoma

RIPA:

Radioimmunoprecipitation assay

RLU:

Relative luciferase

RPMI:

Roswell Park Memorial Institute

RT-qPCR:

Reverse transcription quantitative polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

SH-TAZ:

Short hairpin RNA targeting TAZ

SPF:

Specific pathogen-free

TAZ:

Transcriptional co-activator with PDZ-binding motif

TCGA:

The Cancer Genome Atlas

TPM:

Transcripts per million

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling

WPI:

Whey protein isolate

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Acknowledgements

We would like to give our sincere appreciation to the reviewers for their helpful comments on this study.

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Author notes

  1. Pingfeng Chen, Youjun Duan and Xinsheng Lu Contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, First Affiliated Hospital, University of South China, No. 69, Chuanshan Road, Hengyang, 421001, Hunan Province, People’s Republic of China

    Pingfeng Chen, Youjun Duan, Xinsheng Lu, Libo Chen, Wang Zhang, Hao Wang & Shimin Liu

  2. Department of Radiology, First Affiliated Hospital, University of South China, No. 69, Chuanshan Road, Hengyang, 421001, Hunan Province, People’s Republic of China

    Rong Hu

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Contributions

PFC, YJD, XSL, LBC, RH, WZ, SML, and HW designed the study. PFC, YJD, and XSL collated the data, carried out data analyses, and produced the initial draft of the manuscript. LBC, RH, WZ, SML, and HW contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Rong Hu or Shimin Liu.

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The study protocol was approved by the Medical and Clinical Research Ethics Committee of the First Affiliated Hospital, University of South China, and performed in strict accordance with the Declaration of Helsinki.

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Animal experimental procedures were in line with the animal care guideline of National Institutes of Health. Great efforts were made to minimize the number of animals used in the experiments and their discomfort.

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Chen, P., Duan, Y., Lu, X. et al. RB1CC1 functions as a tumor-suppressing gene in renal cell carcinoma via suppression of PYK2 activity and disruption of TAZ-mediated PDL1 transcription activation. Cancer Immunol Immunother 70, 3261–3275 (2021). https://doi.org/10.1007/s00262-021-02913-8

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