The potential functions of FAM46C in oral squamous cell carcinoma

Zhuang, Xiaohua; Lu, Mengmeng

doi:10.2147/ott.s185244

Cited by 8 publications

(6 citation statements)

References 21 publications

(21 reference statements)

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“…Moreover, FAM46C is reported to physically interact with polo‐like kinase 4 (PLK4) and inhibits its kinase activity, thereby suppressing colorectal cancer in a PAP activity‐independent manner [ 31 ]. The tumor suppressor function of FAM46C is also implicated in prostatic cancer [ 32 ], gastric cancer [ 33 ], hepatocellular carcinoma [ 34 ], and oral squamous cell carcinoma [ 35 ]. Given the close association with MM and other types of cancer, the structural and biochemical features of FAM46C that underlies its cellular function and disease‐related mutations remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

Zhang

et al. 2021

Cancer Communications

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Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of aberrant plasma cells within the bone marrow.The high frequent mutation of family with sequence similarity 46, member C (FAM46C) is closely related with the occurrence and progression of MM.Recently, FAM46C has been identified as a non-canonical poly(A) polymerase (PAP) that functions as a tumor suppressor in MM. This study aimed to elucidate the structural features of this novel non-canonical PAP and how MM-related mutations affect the structural and biochemical properties of FAM46C, eventually advancing our understandings towards FAM46C mutation-related MM occurrence. Methods: We purified and crystallized a mammalian FAM46C construct, and solved its structure. Next, we characterized the property of FAM46C as a PAP through a combination of structural analysis, site-directed mutagenesis and biochemical assays, and by comparison with its homolog FAM46B. Finally, we structurally analyzed MM-related FAM46C mutations and tested the enzymatic activity of corresponding mutants. Results: We determined the crystal structure of a mammalian FAM46C protein at 2.35 Å, and confirmed that FAM46C preferentially consumed adenosine triphosphate (ATP) and extended A-rich RNA substrates. FAM46C showed a weaker PAP activity than its homolog FAM46B, and this difference was largely dependent on the residue variance at particular sites. Of them, residues at positions 77, 290, and 298 of mouse FAM46C were most important for the divergence in enzymatic activity. Among the MM-associated FAM46C mutants, those residing at the catalytic site (D90G and D90H) or putative RNA-binding site (I155L, S156F, D182Y, F184L, Y247V, and M270V) showed abolished or compromised PAP activity of FAM46C, while N72A and S248A did not severely affect the PAP activity. FAM46C mutants D90G, D90H, I155L, S156F, F184L, Y247V, and M270V hadThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

Zhang

et al. 2021

Cancer Communications

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“…Family with sequence similarity 46 member C ( FAM46C ), a non-standard poly(A) polymerase, was found to be a significant crosstalk gene between periodontitis and MS. Previous evidence has shown that FAM46C can inhibit tumor growth through a variety of pathways [ 33 ]. In addition, emerging evidence has shown that FAM46C can regulate immune responses.…”

Section: Discussionmentioning

confidence: 99%

Exploration of potential shared gene signatures between periodontitis and multiple sclerosis

Wu,

Cheng,

Zhang

et al. 2024

BMC Oral Health

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Background Although periodontitis has previously been reported to be linked with multiple sclerosis (MS), but the molecular mechanisms and pathological interactions between the two remain unclear. This study aims to explore potential crosstalk genes and pathways between periodontitis and MS. Methods Periodontitis and MS data were obtained from the Gene Expression Omnibus (GEO) database. Shared genes were identified by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Then, enrichment analysis for the shared genes was carried out by multiple methods. The least absolute shrinkage and selection operator (LASSO) regression was used to obtain potential shared diagnostic genes. Furthermore, the expression profile of 28 immune cells in periodontitis and MS was examined using single-sample GSEA (ssGSEA). Finally, real-time quantitative fluorescent PCR (qRT-PCR) and immune histochemical staining were employed to validate Hub gene expressions in periodontitis and MS samples. Results FAM46C, SLC7A7, LY96, CFI, DDIT4L, CD14, C5AR1, and IGJ genes were the shared genes between periodontitis, and MS. GO analysis revealed that the shared genes exhibited the greatest enrichment in response to molecules of bacterial origin. LASSO analysis indicated that CFI, DDIT4L, and FAM46C were the most effective shared diagnostic biomarkers for periodontitis and MS, which were further validated by qPCR and immunohistochemical staining. ssGSEA analysis revealed that T and B cells significantly influence the development of MS and periodontitis. Conclusions FAM46C, SLC7A7, LY96, CFI, DDIT4L, CD14, C5AR1, and IGJ were the most important crosstalk genes between periodontitis, and MS. Further studies found that CFI, DDIT4L, and FAM46C were potential biomarkers in periodontitis and MS.

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“…They used oral SCC cell lines with low or high FAM46C levels and either reexpressed or down-modulated the protein. They found a drastic reduction in proliferation and significant induction in apoptosis when FAM46C was re-expressed and diametrically opposing effects when FAM46C was down-modulated [12].…”

Section: Squamous Cell Carcinomamentioning

confidence: 99%

“…The first functional studies were mostly performed in MM, but later, investigations also involved other cancer types, namely colorectal [9], prostate [10] and gastric cancer [11], and squamous cell [12] and hepatocellular carcinoma [7]. In these scenarios, FAM46C was shown to behave as a tumour suppressor modulating different intracellular pathways important for cell proliferation and survival, namely the MAPK/ERK [7], PI3K/AKT [13], WNT/β-catenin [11] and SMAD [14] pathways.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Puzzling Roles of FAM46C: A Multifaceted Pan-Cancer Tumour Suppressor with Increasing Clinical Relevance

Lai,

De Grossi,

Catusi

et al. 2024

Cancers

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FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in several tumours, significant mutations in the FAM46C gene are only found in multiple myeloma (MM). Consequently, its tumour suppressor activity has primarily been studied in the MM context. However, emerging evidence suggests that FAM46C is involved also in other cancer types, namely colorectal, prostate and gastric cancer and squamous cell and hepatocellular carcinoma, where FAM46C expression was found to be significantly reduced in tumoural versus non-tumoural tissues and where FAM46C was shown to possess anti-proliferative properties. Accordingly, FAM46C was recently proposed to function as a pan-cancer prognostic marker, bringing FAM46C under the spotlight and attracting growing interest from the scientific community in the pathways modulated by FAM46C and in its mechanistic activity. Here, we will provide the first comprehensive review regarding FAM46C by covering (1) the intracellular pathways regulated by FAM46C, namely the MAPK/ERK, PI3K/AKT, β-catenin and TGF-β/SMAD pathways; (2) the models regarding its mode of action, specifically the poly(A) polymerase, intracellular trafficking modulator and inhibitor of centriole duplication models, focusing on connections and interdependencies; (3) the regulation of FAM46C expression in different environments by interferons, IL-4, TLR engagement or transcriptional modulators; and, lastly, (4) how FAM46C expression levels associate with increased/decreased tumour cell sensitivity to anticancer agents, such as bortezomib, dexamethasone, lenalidomide, pomalidomide, doxorubicin, melphalan, SK1-I, docetaxel and norcantharidin.

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The potential functions of FAM46C in oral squamous cell carcinoma

Cited by 8 publications

References 21 publications

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

Exploration of potential shared gene signatures between periodontitis and multiple sclerosis

Dissecting the Puzzling Roles of FAM46C: A Multifaceted Pan-Cancer Tumour Suppressor with Increasing Clinical Relevance

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