Transcriptionally up-regulation of CDKN1A/p21 by TFE3 fusion proteins worsened TFE3-rearranged renal cell carcinoma

The TFE3-rearranged renal cell carcinoma (TFE3-rRCC), which is an uncommon and aggressive form of kidney cancer, has an unfavorable prognosis. It has been shown that CDKN1A/p21 is high-expressed in TFE3-rRCC, however, the exact mechanism and the role of CDKN1A/p21 in TFE3-rRCC remain unclear. Our results indicated that the TFE3 fusions exacerbated TFE3-rRCC by transcriptionally upregulating CDKN1A/p21 expression. In terms of the mechanism, CDKN1A/p21 was a target gene of TFE3 fusions with positive regulation. Activation of AKT led to the cytoplasmic localization of highly expressed CDKN1A/p21, promoting TFE3-rRCC progression by anti-apoptosis and facilitating migration. Additionally, the remaining nuclear CDKN1A/p21 induced cellular senescence (CS) and secretion of senescence-associated secretory phenotype (SASP) factors, particularly IL-6 and IL-8, which recruited inhibitory immune cells and remodeled tumor microenvironment. This research presents that upregulation of CDKN1A/p21 transcriptionally by TFE3 fusions facilitates the progression of TFE3-rRCC by inducing anti-apoptosis, migration and CS, thus provides a promising target for treating TFE3-rRCC.