Abstract
Cellular senescence evasion caused by the inactivation of tumor suppressive programs is implicated in tumor initiation and therapeutic resistance. Our previous study has shown that the downregulation of growth arrest and DNA damage 45G (GADD45G) contributes to senescence bypass in hepatocellular carcinoma (HCC). Here, we report that the Smad-interacting protein-1 (SIP1) is transcriptionally activated and functions critically in the GADD45G-induced tumor cell senescence. Knockdown of SIP1 significantly abrogates the suppressive effects of GADD45G on the growth of xenografted liver tumor in vivo. The essential role of SIP1 in GADD45G activities is further validated in the model of the proteasome inhibitor MG132-induced cell senescence. We further show that JNK but not p38 MAPK activation is involved in the GADD45G-mediated SIP1 upregulation, and that JNK inhibition counteracts the GADD45G-induced cellular senescence. More importantly, we show that GADD45G and SIP1 expression are coincidently downregulated in primary human HCC tissues. Together, our results establish that the dowregulation of GADD45G-SIP1 axis may contribute to cellular senescence evasion and HCC development.
Highlights
Hepatocellular carcinoma (HCC), a highly lethal cancer, is one of the most common tumors worldwide
Our observations show that Smad-interacting protein-1 (SIP1) induction is essential for the stress sensor GADD45G-mediated tumor cell senescence, and that the GADD45G-SIP1 axis is downregulated in clinical HCC
SIP1, a member of the δ-crystallin enhancer binding factor 1 family, is initially recognized as a two-handed zinc finger transcription factor that binds to Smad1, which plays a critical role in TGF-β signaling and the bone morphogenetic protein (BMP) pathway [32, 33]
Summary
Hepatocellular carcinoma (HCC), a highly lethal cancer, is one of the most common tumors worldwide. HCC tumor cells are believed to bypass hepatocellular senescence to gain immortality [4]. HCC is one of the major tumors displaying p53 mutations and p16INK4a inactivation [5]. Downregulation of p16 via DNA methylation is responsible for Hepatitis C virus Core protein to overcome stress-induced premature senescence in HCC [6]. Studies have shown that senescence process can be reactivated in HCC cells if the protumorigenic events are inactivated. The suppression of c-myc oncogene results in tumor regression by inducing premature senescence in murine HCCs [7]. MiR-34a regulates cellular senescence through the modulation of telomere pathway by targeting the c-Myc and FoxM1 gene in HCC tissues and cell lines [8]. In addition to the functional defeats in the classical cell cycle check-points, such as p53, retinoblastoma (Rb), and INK4a-ARF, the dys-regulation of nonclassical senescence inducers, as an independent or a complementary mechanism, may be required for senescence evasion and efficient tumorigenesis [9,10,11,12]
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