Re-Expression of Transcription FactorATF5in Hepatocellular Carcinoma Induces G2-M Arrest

Abstract

Transcription factors represent an important class of genes that play key roles in controlling cellular proliferation, cell cycle modulation, and attractive targets for cancer therapy. Here, we report on the novel finding of common ATF5 downregulations in hepatocellular carcinoma (HCC), a highly malignant tumor with a dismal clinical course. Array-based mapping in HCC highlighted a high and consistent incidence of transcription factor ATF5 repressions on regional chr.19q13. By quantitative reverse transcription-PCR, profound down-regulations of ATF5 were further suggested in 78% of HCC tumors (60 of 77 cases) compared to their adjacent nontumoral liver (P = 0.0004). Restoration of ATF5 expression in 3 nonexpressing HCC cell lines demonstrated a consistent growth inhibitory effect (P < 0.029) but minimal induction on cellular apoptosis. Subsequent flow cytometric investigations revealed a G 2 -M cell cycle arrest in HCC cells that were ectopically transfected with ATF5 (P < 0.002). The differential expressed genes from the functional effects of ATF5 were examined by array profiling. Over a hundred genes were identified, among which ID1 contains the ATF/CREB target binding sequences within its promoter region. An inverse relationship between ATF5 expressions with ID1 transcriptions was verified in HCC (P = 0.019), and a direct interaction of ATF5 on the promoter of ID1 was further demonstrated from electromobility shift assay. Examination of causal events underlying the silencing of ATF5 in HCC suggested copy number losses, promoter hypermethylation, histone deacetylation, and DNA mutations to be the likely inactivating mechanisms. In conclusion, our finding supports a tumor suppressive role for ATF5 in HCC, and highlighted ID1 as a potential downstream target. [Cancer Res 2008; 68(16):6743-51]

Overexpression of activating transcription factor 5 in human rectal cancer

“…These observations suggest that ATF5 may be an attractive target for therapeutic intervention in such tumor types. Consistent with these findings, ATF5 is highly expressed in a wide variety of neoplasms, including renal cell cancer, lung cancer, lymphomas, seminomas, cervical cancer, prostate cancer, hematopoietic carcinoma and hepatocellular carcinoma (17,20,25,26).…”

“…Transcription factor ATF5, an ATF/CREB family member and bZIP protein, functions as a cancer-specific cell survival factor and promotes survival of cancer cells (22,32). Although evidence has been presented that ATF5 is involved in the onset and progression of cancer (20)(21)(22)(23)(24)(25)(26), no study, to the best of our knowledge, has reported whether ATF5 is related to rectal cancer. In the present study, the ATF5 protein and mRNA expression in human rectal carcinoma and normal tissue was analyzed using immunohistochemistry and RT-PCR.…”

“…ATF5 has been associated with cell differentiation, proliferation and survival in several tissues and cell types (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). It may be a potent repressor of p53 and its elevated expression may be related to enhanced malignant phenotypes (21).…”

An Activating Transcription Factor 5-Mediated Survival Pathway as a Target for Cancer Therapy

“…Similarly, a query of the Oncomine cancer profiling database revealed that, in general, the expression level of ATF5 is significantly higher in malignant tissues than their normal counterpart tissues [11]. The only exception appears to be hepatocellular carcinoma cells, which express lower levels of ATF5 than normal liver cells; this discrepancy may be due to epigenetic silencing of ATF5 in hepatocellular carcinoma cells through promoter methylation [12]. Notably, increased levels of ATF5 have been observed in primary brain tumors, and ATF5 expression is particularly high in glioblastoma, an aggressive form of malignant glioma [10,11].…”

Cell Type-Dependent Function of Atf5: Where We Go from Here

“…The activating transcription factor 5 (ATF5 or ATFx) is a member of the ATF/CREB transcription factor family. Although ATF5 is known to regulate cell cycle progression [4][5][6][7], cell survival [5][6][7][8][9][10][11][12][13], autophagy [14], cell fate determination [15][16][17] and cellular stress response [13][14][15][16][17][18][19], and it is likely involved in the development of schizophrenia [20][21][22] and chronic lymphocytic leukemia [23], only a few of its targets have been reported and the mechanism of ATF5 function remains largely unknown and occasionally controversial.Previous reports have shown that ATF5 enhances cell survival and proliferation of glioma, breast cancer cells and neuroprogenitor cells [5,[10][11][12]24] while eliciting a G2/M blockade in hepatocellular carcinoma cells [4,6]. ATF5 acts as a pro-survival factor in HeLa and hematopoietic FL5.12 cells [8] but may also increase cisplatin-induced apoptosis through up-regulation of cyclin D3 in HeLa cells [25].…”