en Cellular and Molecular Biology پژوهشي Research <p dir="auto"></p> <div style="text-align: justify;"><span style="font-size:12px;"><span style="font-family:Times New Roman;"><b>Background:</b> Colorectal cancer (CRC) is a leading cause of cancer-related mortality, underscoring the need for novel therapies targeting key drivers of tumor progression. Telomerase, which is reactivated in 85 - 90% of CRCs, confers unlimited replicative potential and represents a promising therapeutic target. Valproic acid (VPA), a histone deacetylase inhibitor with documented anticancer properties, has unclear effects on telomerase activity and human telomerase reverse transcriptase (hTERT) expression in CRC.<br> <b>Methods:</b> Six human CRC cell lines (HCT116, HT-29/219, LS180, SW1116, SW480, and SW742) were treated with 1.5 mM VPA for 72 hours. Telomerase activity was evaluated using a non-isotopic TRAP assay in both intact cells and cell-free systems. hTERT mRNA expression was quantified by real-time RT-PCR and normalized to GAPDH using the 2-&Delta;&Delta;Ct method. Statistical significance was assessed using the t-test or ANOVA, with P < 0.05 considered statistically significant.<br> <b>Results:</b> VPA significantly reduced telomerase activity in SW480 (27.7 &plusmn; 6.24%), SW742 (33.2 &plusmn; 12.34%), HT-29/219 (18.6 &plusmn; 4.6%), and LS180 (21.8 &plusmn; 5.32%) cells (P < 0.05), but not in HCT116 or SW1116 cells. No inhibition was observed in cell-free systems treated with 1.5 - 5 mM VPA, indicating an indirect mechanism of action. hTERT mRNA expression was significantly downregulated in HCT116 (38.0 &plusmn; 8%), LS180 (49.3 &plusmn; 10.18%), and HT-29/219 (34.8 &plusmn; 14.2%) cells (P < 0.05), while changes in the remaining cell lines were not statistically significant.<br> <b>Conclusion</b>: VPA indirectly inhibits telomerase activity in a subset of CRC cell lines, primarily through transcriptional repression of hTERT. These findings suggest that transcriptional regulation is a key underlying mechanism, although post-transcriptional or post-translational processes may also contribute in a cell line-specific manner. Overall, the results highlight the therapeutic potential of VPA for targeting telomerase in CRC, particularly as part of combination strategies with telomere-shortening agents.</span></span></div> Colorectal Cancer, Valproic Acid, Telomerase, Human Telomerase Reverse Transcriptase 12 16 http://jcbr.goums.ac.ir/browse.php?a_code=A-10-391-1&slc_lang=en&sid=1 Mohsen Tatar mohsentatar@ymail.com 10031947532846006625 10031947532846006625 Yes Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Fatemeh Lotfi Asrami ftm.la7899@gmail.com 10031947532846006626 0009-0004-5185-3318 No Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran Mehdi Khorami mohrazofficial@gmail.com 10031947532846006627 10031947532846006627 No Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran Fakhraddin Naghibalhossaini fakhraddin.naghibalhossaini@mail.mc 10031947532846006628 10031947532846006628 No Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran