SIX1 Activation Is Involved in Cell Proliferation, Migration, and Anti-inflammation of Acute Ischemia/Reperfusion Injury in Mice

Abstract

Nephrogenic proteins are re-expressed after ischemia/reperfusion (I/R) injury; however, the role of these proteins is still unknown. We found that sine oculis homeobox 1 (SIX1), a developmentally regulated homeoprotein, is reactivated in tubular epithelial cells after I/R injury associated with cell proliferation/migration and anti-inflammation. We demonstrated that SIX1 promoted cell proliferation by upregulating cyclin and glycolytic genes, and might increase cell migration by upregulating the expression of matrix metalloproteinase 9 (MMP9) directly or indirectly in the cell model. Notably, SIX1 targeted the promoters of the amino-terminal enhancer of split (AES) and fused in sarcoma (FUS), which are cofactors of nuclear factor-κB (NF-κB) subunit RELA, and then inhibited the transactivation function of RELA. The expression of monocyte chemotactic protein-1 (MCP-1) was decreased by the SIX1-mediated NF-κB pathway. Our results showed that the expression of cyclin, glycolytic genes, and MMP9 were significantly increased, and the infiltration of monocytes/macrophages (Mophs) was suppressed in SIX1 overexpression kidney at 1, 2, and 3 days after reperfusion. The overexpression of SIX1 resulted in reducing kidney damage from I/R injury in mice by promoting cell proliferation and migration and by inhibiting inflammation. Our study provides evidence that SIX1 involved in cell proliferation, migration, and anti-inflammation in the I/R model, which might be a potential therapeutic target that could be used to ameliorate kidney damage.

Developmental regulators drive DUX4 expression in facioscapulohumeral muscular dystrophy

“…S4A). To determine if SIX transcription factors were otherwise active in myoblasts, we looked at the expression of known targets of SIX1 ( PGK1, SLC4A7 ) and SIX2 ( EYA1 , SLC4A7 ) (Gu et al 2016; Li et al 2018; Jin et al 2021). Knockdown of SIX1 resulted in a 26% decrease in PGK1 RNA levels and a 46% decrease in SLC4A7 RNA levels (Fig.…”

Both a hypoxia-inducible EYA3 and a histone acetyltransferase p300 function as coactivators of SIX5 to mediate tumorigenesis and cancer progression

“…Mammalian genomes encode 6 sine oculis homeobox genes (SIXs) characterized by the presence of the SIX domain ( 5 ). The SIX family proteins function as transcription factors to regulate embryogenesis by controlling the renewal and differentiation of progenitor cells ( 5 , 6 ). Following the complement of development, SIXs are typically downregulated ( 5 , 6 ).…”

“…The SIX family proteins function as transcription factors to regulate embryogenesis by controlling the renewal and differentiation of progenitor cells ( 5 , 6 ). Following the complement of development, SIXs are typically downregulated ( 5 , 6 ). In recent years, SIX family proteins, especially SIX1, have been identified as being overexpressed in multiple cancers, such as breast cancer, ovarian cancer, prostate cancer, and CRC ( 7 - 10 ).…”