Search Results (5)

The zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) has emerged as a critical regulator of diverse cellular processes, including autophagy, cell cycle progression, and tumorigenesis. Structurally, ZKSCAN3 is characterized by its conserved DNA-binding zinc finger motifs, a SCAN domain mediating protein–protein interaction, and a KRAB repression domain implicated in transcriptional regulation. Post-translational modifications, such as phosphorylation and ubiquitination, dynamically modulate its subcellular localization and activity, enabling context-dependent functional plasticity. Functionally, ZKSCAN3 acts as a master switch in autophagy by repressing the transcription of autophagy-related genes under nutrient-replete conditions, while its nuclear-cytoplasmic shuttling under stress conditions links metabolic reprogramming to cellular survival. Emerging evidence also underscores its paradoxical roles in cancer: it suppresses tumor initiation by maintaining genomic stability yet promotes metastasis through epithelial–mesenchymal transition induction. Furthermore, epigenetic mechanisms, including promoter methylation and non-coding RNA regulation, fine-tune ZKSCAN3 expression, contributing to tissue-specific outcomes. Despite these insights, gaps remain in understanding the structural determinants governing its interaction with chromatin-remodeling complexes and the therapeutic potential of targeting ZKSCAN3 in diseases. Future investigations should prioritize integrating multi-omics approaches to unravel context-specific regulatory networks and explore small-molecule modulators for translational applications. This comprehensive analysis provides a framework for advancing our mechanistic understanding of ZKSCAN3 and its implications in human health and disease. This review synthesizes recent advances in elucidating the regulatory networks and functional complexity of ZKSCAN3, highlighting its dual roles in physiological and pathological contexts. Full article

ZKSCAN3 (also known as ZNF306) plays a pivotal role in the regulation of various cellular processes that are fundamental to the development of cancer. It has been widely acknowledged as a key contributor to cancer progression, with its overexpression consistently reported in a broad spectrum of malignancies. Importantly, clinical studies have demonstrated a significant association between elevated ZKSCAN3 levels and adverse prognosis, as well as resistance to therapeutic drugs. Specifically, ZKSCAN3 promotes tumor progression by enhancing multiple hallmark features of cancer and promoting the acquisition of cancer-specific phenotypes. These effects manifest as increased tumor cell proliferation, invasion, and metastasis, accompanied by inhibiting tumor cell apoptosis and modulating autophagy. Consequently, ZKSCAN3 emerges as a promising prognostic marker, and targeting its inhibition represents a potential strategy for anti-tumor therapy. In this review, we provide an updated perspective on the role of ZKSCAN3 in governing tumor characteristics and the underlying molecular mechanisms. Furthermore, we underscore the clinical relevance of ZKSCAN3 and its potential implications for tumor prognosis and therapeutic strategies. Full article

Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) acts as an oncogenic transcription factor in human malignant tumors, including colon and prostate cancer. However, most of the ZKSCAN3-induced carcinogenic mechanisms remain unknown. In this study, we identified ZKSCAN3 as a downstream effector of the oncogenic Wnt/β-catenin signaling pathway, using RNA sequencing and ChIP analyses. Activation of the Wnt pathway by recombinant Wnt gene family proteins or the GSK inhibitor, CHIR 99021 upregulated ZKSCAN3 expression in a β-catenin-dependent manner. Furthermore, ZKSCAN3 upregulation suppressed the expression of the mitotic spindle checkpoint protein, Mitotic Arrest Deficient 2 Like 2 (MAD2L2) by inhibiting its promoter activity and eventually inducing chromosomal instability in colon cancer cells. Conversely, deletion or knockdown of ZKSCAN3 increased MAD2L2 expression and delayed cell cycle progression. In addition, ZKSCAN3 upregulation by oncogenic WNT/β-catenin signaling is an early event of the adenoma–carcinoma sequence in colon cancer development. Specifically, immunohistochemical studies (IHC) were performed using normal (NM), hyperplastic polyps (HPP), adenomas (AD), and adenocarcinomas (AC). Their IHC scores were considerably different (61.4 in NM; 88.4 in HPP; 189.6 in AD; 246.9 in AC). In conclusion, ZKSCAN3 could be responsible for WNT/β-catenin-induced chromosomal instability in colon cancer cells through the suppression of MAD2L2 expression. Full article

Lysosomes are important for proper functioning of the retinal pigment epithelial (RPE) cells. RPE cells have a daily burden of phagocytosis of photoreceptor outer segments (POS) and also degrade cellular waste by autophagy. Here, we identified the role of Zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3) in co-ordinate regulation of lysosomal function and autophagy in the RPE. Our studies show that in the RPE, ZKSCAN3 is predominantly nuclear in healthy cells and its nuclear expression is reduced upon nutrient deprivation. siRNA-mediated knockdown of ZKSCAN3 results in de-repression of some of the ZKSCAN3 target genes. Knockdown of ZKSCAN3 also resulted in an induction in autophagy flux, increase in the number of functional lysosomes and accompanied activation of lysosomal cathepsin B activity in ARPE-19 cells. We also demonstrated that inhibition of P38 mitogen-activated protein kinase (MAPK) retains ZKSCAN3 in the nucleus in nutrient-deprived cells. In summary, our studies elucidated the role of ZKSCAN3 as a transcriptional repressor of autophagy and lysosomal function in the RPE. Full article

Zinc finger with KRAB and SCAN domain 3 (ZKSCAN3) upregulates genes encoding proteins involved in cell differentiation, proliferation and apoptosis. ZKSCAN3 has been reported to be overexpressed in several human cancers such as colorectal cancer and prostate cancer and is proposed as a candidate oncoprotein. However, the molecular mechanism by which ZKSCAN3 participates in carcinogenesis is largely unknown. Here, we evaluated ZKSCAN3 expression in uterine cervical cancers (CC) by immunohistochemistry using formalin-fixed, paraffin-embedded tissues from 126 biopsy samples from 126 patients. The clinicopathological findings were analyzed and compared with ZKSCAN3 expression levels. ZKSCAN3 was strongly overexpressed in CCs compared to adjacent non-neoplastic cervical mucosa tissues. Moreover, a gene copy number assay showed amplified ZKSCAN3 in CC samples. ZKSCAN3 overexpression was also significantly associated with poor overall survival of the patients. Overall, our findings indicate that ZKSCAN3 overexpression is a frequent event in uterine CC and is correlated with a poor clinical outcome. ZKSCAN3 could be developed as a molecular marker for prognostic prediction and early detection. Full article