# SET8 inhibition preserves PTEN to attenuate kidney cell apoptosis in cisplatin nephrotoxicity

## TL;DR

Inhibiting SET8 protects kidney cells from cisplatin damage by preserving PTEN, reducing cell death and DNA damage.

## Contribution

This study reveals a novel protective mechanism of SET8 inhibition in cisplatin-induced kidney injury through PTEN preservation.

## Key findings

- SET8 inhibition with UNC0379 reduces kidney cell apoptosis and DNA damage in cisplatin-induced AKI.
- PTEN preservation by SET8 inhibition restores autophagy and reduces DDR in renal cells.
- Blocking PTEN negates the protective effects of SET8 inhibition, confirming PTEN's role in the mechanism.

## Abstract

The aberrant expression of SET8, a histone methyltransferase that mediates H4
lysine 20 mono-methylation (H4K20me1), is implicated in the pathogenesis of various
tumors, however, its role in acute kidney injury (AKI) is unknown. Here we showed that
SET8 and H4K20me1 were upregulated in the murine kidney with AKI induced by cisplatin,
along with increased renal tubular cell injury and apoptosis and decreased expression of
E-cadherin and Phosphatase and Tensin Homolog (PTEN). Suppression of SET8 by UNC0379
improved renal function, attenuated tubule damage, and restored expression of PTEN, but
not E-cadherin. UNC0379 was also effective in lessening cisplatin-induced DNA damage
response (DDR) as indicated by reduced expression of γ-H2AX, p53, p21, and
alleviating cisplatin-impaired autophagy as shown by retained expression of Atg5,
Beclin-1, and CHMP2A and enhanced levels of LC3-II in the kidney. Consistently, inhibition
of SET8 with either UNC0379 or siRNA mitigated apoptosis and DDR, and restored autophagy,
along with PTEN preservation in cultured renal proximal tubular epithelial cell (TKPTs)
exposed to cisplatin. Further studies showed that inhibition of PTEN with Bpv or siRNA
potentiated cisplatin-induced apoptosis, DDR, and hindered autophagy, and conversely,
alleviated by overexpression of PTEN in TKPTs. Finally, blocking PTEN largely abolished
the inhibitory effect of UNC0379 on apoptosis. Taken together, these results suggest that
SET8 inhibition protects against cisplatin-induced AKI and renal cell apoptosis through a
mechanism associated with the preservation of PTEN, which in turn inhibits DDR and
restores autophagy.