STAT3 phosphorylation at serine 727 activates specific genetic programs and promotes clear cell renal cell carcinoma (ccRCC) aggressiveness

Abstract

Cancer models; Molecular medicine

Modelos de cáncer; Medicina molecular

Models de càncer; Medicina molecular

The signal transducer and activator of transcription 3 (STAT3) is a transcription factor mainly activated by phosphorylation in either tyrosine 705 (Y705) or serine 727 (S727) residues that regulates essential processes such as cell differentiation, apoptosis inhibition, or cell survival. Aberrant activation of STAT3 has been related to development of nearly 50% of human cancers including clear cell renal cell carcinoma (ccRCC). In fact, phosho-S727 (pS727) levels correlate with overall survival of ccRCC patients. With the aim to elucidate the contribution of STAT3 phosphorylation in ccRCC development and progression, we have generated human-derived ccRCC cell lines carrying STAT3 Y705 and S727 phosphomutants. Our data show that the phosphomimetic substitution Ser727Asp facilitates a pro-tumoral phenotype in vitro, in a Y705-phosphorylation-independent manner. Moreover, we describe that STAT3 phosphorylation state determines the expression of different subsets of target genes associated with distinct biological processes, being pS727-dependent genes the most related to cellular hallmarks of cancer. In summary, the present study constitutes the first analysis on the role of overall STAT3 phosphorylation state in ccRCC and demonstrates that pS727 promotes the expression of a specific subset of target genes that might be clinically relevant as novel biomarkers and potential therapeutic targets for ccRCC.

This work was supported by Ministerio de Ciencia e Innovación (Grant No. SAF201459945-R and SAF2017-89989-R) to A.M.; American Association for Cancer Research (AACR, Ref #419589) to A.M. and Red de Investigación Renal REDinREN (Grant No. 12/0021/0013) to. A.M. The group holds the Quality Mention from the Generalitat de Catalunya (Grant No. 2021 SGR 01,600). J.A. was a recipient of the Ph.D. Fellow Program from Consejo Nacional de Ciencia y Tecnología (CONACyT), México (Grant No. 549678).