Loss of hepatic Sirt7 accelerates diethylnitrosamine (DEN)-induced formation of hepatocellular carcinoma by impairing DNA damage repair
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The mammalian sirtuin family (SIRT1–SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the leaststudied sirtuin, has been demonstrated to be a key factor forDNA damage response (DDR). However, conflicting resultshave proposed that Sirt7 is an oncogenic factor to promotetransformation in cancer cells. To address this inconsistency, weinvestigated properties of SIRT7 in hepatocellular carcinoma(HCC) regulation under DNA damage and found that loss ofhepatic Sirt7 accelerated HCC progression. Specifically, thenumber, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedlyenhanced. Further, levels of HCC progression markers andpro-inflammatory cytokines were significantly elevated in theabsence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site byinhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNAdamage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike earlystudies describing that Sirt7 is an oncogenic factor.
Abstract
The mammalian sirtuin family (SIRT1–SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the leaststudied sirtuin, has been demonstrated to be a key factor forDNA damage response (DDR). However, conflicting resultshave proposed that Sirt7 is an oncogenic factor to promotetransformation in cancer cells. To address this inconsistency, weinvestigated properties of SIRT7 in hepatocellular carcinoma(HCC) regulation under DNA damage and found that loss ofhepatic Sirt7 accelerated HCC progression. Specifically, thenumber, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedlyenhanced. Further, levels of HCC progression markers andpro-inflammatory cytokines were significantly elevated in theabsence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site byinhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNAdamage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike earlystudies describing that Sirt7 is an oncogenic factor.
참고문헌 (45)
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