Family with sequence similarity 111 member B contributes to tumor growth and metastasis by mediating cell proliferation, invasion, and EMT via transforming acidic coiled-coil protein 3/PI3K/AKT signaling pathway in hepatocellular carcinoma.

As a complex systemic disease, primary liver cancer ranks third in death rate for solid tumors worldwide. Family with sequence similarity 111 member B (FAM111B), which was found to be aberrantly mutated in multiple cancers, is a candidate oncogene. We aimed to determine the function and mechanism of FAM111B in hepatocellular carcinoma (HCC). The expression of FAM111B was evaluated in HCC tissues, adjacent tissues, HCC cell lines. The impact of FAM111B on proliferation, invasion, apoptosis and EMT of HCC cells were detected by CCK-8, Transwell, flow cytometry and Western blot assays. The relationship between FAM111B and transforming acidic coiled-coil protein 3 (TACC3) was assessed by CoIP and Immunofluorescence (IF) staining assays. The effect of FAM111B on tumor growth was detected by using xenograft model of nude mice. The expression of FAM111B was upregulated in HCC tissues and cell lines, and the prognosis of HCC patients was worse in the high FAM111B expression group, and its expression level was associated with the TNM stage of HCC. FAM111B silencing inhibited HCC cell proliferation and invasion, EMT and induced apoptosis. Besides, TACC3 served as an interactor for FAM111B, which could enhance TACC3 expression, thus activing PI3K/AKT pathway. Rescue experiments revealed that elevated of TACC3 restored the inhibitory effect of FAM111B overexpression on the cell functions via PI3K/AKT pathway. In vivo, FAM111B inhibition hampered tumor growth and metastasis of HCC. This study highlighted a key player of FAM111B in modulating the malignant biological progression of HCC via TACC3/PI3K/AKT signaling pathway, displaying a potential therapeutic target for HCC.

Unravelling the Intricate Roles of FAM111A and FAM111B: From Protease-Mediated Cellular Processes to Disease Implications.

Proteases are critical enzymes in cellular processes which regulate intricate events like cellular proliferation, differentiation and apoptosis. This review highlights the multifaceted roles of the serine proteases FAM111A and FAM111B, exploring their impact on cellular functions and diseases. FAM111A is implicated in DNA replication and replication fork protection, thereby maintaining genome integrity. Additionally, FAM111A functions as an antiviral factor against DNA and RNA viruses. Apart from being involved in DNA repair, FAM111B, a paralog of FAM111A, participates in cell cycle regulation and apoptosis. It influences the apoptotic pathway by upregulating anti-apoptotic proteins and modulating cell cycle-related proteins. Furthermore, FAM111B's association with nucleoporins suggests its involvement in nucleo-cytoplasmic trafficking and plays a role in maintaining normal telomere length. FAM111A and FAM111B also exhibit some interconnectedness and functional similarity despite their distinct roles in cellular processes and associated diseases resulting from their dysfunction. FAM111A and FAM111B dysregulation are linked to genetic disorders: Kenny-Caffey Syndrome type 2 and Gracile Bone Dysplasia for FAM111A and POIKTMP, respectively, and cancers. Therefore, the dysregulation of these proteases in diseases emphasizes their potential as diagnostic markers and therapeutic targets. Future research is essential to unravel the intricate mechanisms governing FAM111A and FAM111B and explore their therapeutic implications comprehensively.

Identification of Tumor Suppressive miR-144-5p Targets: FAM111B Expression Accelerates the Malignant Phenotypes of Lung Adenocarcinoma.

Accumulating evidence suggests that the passenger strands microRNAs (miRNAs) derived from pre-miRNAs are closely involved in cancer pathogenesis. Analysis of our miRNA expression signature of lung adenocarcinoma (LUAD) and The Cancer Genome Atlas (TCGA) data revealed that miR-144-5p (the passenger strand derived from pre-miR-144) was significantly downregulated in LUAD tissues. The aim of this study was to identify therapeutic target molecules controlled by miR-144-5p in LUAD cells. Ectopic expression assays demonstrated that miR-144-5p attenuated LUAD cell aggressiveness, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. A total of 18 genes were identified as putative cancer-promoting genes controlled by miR-144-5p in LUAD cells based on our in silico analysis. We focused on a family with sequence similarity 111 member B (FAM111B) and investigated its cancer-promoting functions in LUAD cells. Luciferase reporter assay showed that expression of FAM111B was directly regulated by miR-144-5p in LUAD cells. FAM111B knockdown assays showed that LUAD cells significantly suppressed malignant phenotypes, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. Furthermore, we investigated the FAM111B-mediated molecular networks in LUAD cells. Identifying target genes regulated by passenger strands of miRNAs may aid in the discovery of diagnostic markers and therapeutic targets for LUAD.

A Novel De Novo Frameshift Pathogenic Variant in the FAM111B Resulting in Progressive Osseous Heteroplasia Phenotype.

INTRODUCTION: Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. While 60-70% of the POH patients have paternally inherited, inactivating pathogenic variants in GNAS, the remaining 30-40% have no known etiology. FAM111B pathogenic variants, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a very rare, autosomal-dominant disorder with high frequency of de novo missense pathogenic variants, which affects multiple tissues and organs, causing extensive fibrosis and muscle adiposis, though the exact mechanism is unknown. To our knowledge, there are no reports of FAM111B associated with POH. We describe the first case of POH phenotype associated with a novel de novo frameshift pathogenic variant in the FAM111B and present an analysis of the protein structure and function caused by this genomic disruption. CASE: A 15-year-old African-American male presented with generalized calcific nodules, progressive contractures, and muscle weakness leading to immobility, beginning at 6 years of age. Cutaneous examination showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs and computed tomography (CT) of the chest, abdomen, and pelvis showed extensive soft tissue and muscle heterotopic ossifications involving shoulders, axillae, trunk, abdomen, pelvis, upper and lower extremities, in a clumped, conglomerate distribution within muscle, subcutaneous fat, and in some areas extending to the skin. There was no pulmonary fibrosis on the chest CT. The clinical and radiographic findings were most consistent with POH. A trio-clinical exome sequencing revealed a de novo heterozygous likely pathogenic variant in the FAM111B (OMIM # 615584) (c.1462delT [p.Cys488Valfs*21]). The resulted frameshift change in exon 4 replaced C-terminal region with 21 alternative amino acids. Multiple, previously reported disease-associated variants appear to localize within the trypsin-like cysteine/serine peptidase domain in which this variant occurs, supporting the functional significance of this region, though none have been previously reported to be associated with POH phenotype. Our 3D protein modeling showed obliteration of predicted protein folding and structure, and elimination of the zinc-binding domain, likely severely affecting protein function. CONCLUSION: This is the first case of POH phenotype associated with a novel de novo pathogenic frameshift variant in FAM111B. Whether the frameshift change in FAM111B predicts POH remains unclear. Further evaluations are necessary to fully elucidate this finding and the potential role and mechanism by which the FAM111B variants contributes to POH phenotype.

Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases.

Mutations in the human FAM111B gene are associated with a rare, hereditary multi-systemic fibrosing disease, POIKTMP. To date, there are ten POIKTMP-associated FAM111B gene mutations reported in thirty-six patients from five families globally. To investigate the clinical significance of these mutations, we summarized individual cases by clinical features and position of the reported FAM111B gene mutations as those within and outside the putative protease domain (MWPPD and MOPPD respectively). MWPPD cases had more clinical manifestations than MOPPD (25 versus 18). Although the most common clinical features of poikiloderma, alopecia and hypohidrosis overall occurred in 94%, 86% and 75% of all cases with no significant differences between the MOPPD and MWPPD group, less common features included life-threatening (pulmonary fibrosis 47% vs. 13%; liver abnormalities specifically cirrhosis 26% vs. 7%) and physically disabling conditions (myopathy 53% vs. 20%; tendon contracture 55% vs. 7%) were more common in MWPPD cases. Similarly, the only 2 cases of POIKTMP with fatal pancreatic cancers were both only in the MWPPD group. This review thus suggests that mutations within the putative protease domain of the FAM111B protein are associated with a broader range of clinical features and may predict increased POIKTMP severity and a poorer prognosis.

Expanding phenotype of FAM111B-related disease focusing on liver involvement: Literature review, report of a case with end-stage liver disease and proposal for a new acronym.

POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis is a congenital multisystem disorder due to FAM111B dominant variants. We present a literature review focusing on the frequency and the impact of hepatic involvement and a case report of a patient with severe end-stage liver disease. Whole exome sequencing (WES) was conducted on the proband and his parents. A de novo FAM111B: c.1879A > G; (p.Arg627Gly) variant was identified. Hepatic involvement is present in 11 out of the 30 patients described in the literature, with different levels of dysfunction ranging from mild transaminitis to liver fibrosis found in three different cases by liver biopsies. Liver involvement seems to be a significant cause of morbidity. We propose to modify the previous acronym in POIK-TMPL: including POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis/pancreas insufficiency and cancer, liver involvement/lymphedema. Moreover, we suggest screening patients with FAM111B variants for liver involvement from the first month of life and continue with an appropriate follow-up. Further studies are needed to better understand this frequent complication.

Clinicopathological features, prognostic significance, and associated tumor cell functions of family with sequence similarity 111 member B in pancreatic adenocarcinoma.

BACKGROUD: Among digestive tract tumors, pancreatic adenocarcinoma (PAAD) has a high degree of malignancy. Therefore, it is important to search for pancreatic adenocarcinoma-related differential genes and new oncogene therapeutic targets for early diagnosis, treatment, and prognosis of pancreatic adenocarcinoma. AIMS: This study aims to investigate the expression and clinical significance of Family with sequence similarity 111 member B (FAM111B) in PAAD. MATERIALS & METHODS: Bioinformatics was used to analyze the relationship between FAM111B expression and pancreatic adenocarcinoma and to predict its role in related pathways. Tissue microarrays were used to assess the levels of FAM111B in pancreatic cancer tissues by immunohistochemical staining, and the effects of FAM111B expression levels on apoptosis, proliferation, invasion and migration of tumor cells were observed and verified by in vitro cellular assays. RESULTS: FAM111B expression was higher in PAAD tissue than in matched normal tissues (p < 0.05). The expression level of FAM111B, the metastatic status of lymph nodes was an independent prognostic factor for PAAD survival (p < 0.05). Meanwhile, overexpression of FAM111B promoted PAAD cell proliferation, migration, invasion and inhibited PAAD cell apoptosis (p < 0.05). In contrast, knockdown of FAM111B triggered the opposite result (p < 0.05). In the results of GSEA, it was shown that FAM111B may be involved in PAAD progression through p53 signaling pathway, cell cycle, and other signaling pathways (p < 0.05 and FDR q-val <0.25). FAM111B is highly expressed in PAAD tissues and is closely associated with poor prognosis of PAAD. CONCLUSION: FAM111B significantly promotes the proliferation, invasion, and migration of pancreatic adenocarcinoma cells while it inhibits their apoptosis. FAM111B may be a new biomarker for PAAD. It may provide a new direction for the treatment and diagnosis of PAAD.

FAM111B enhances proliferation of KRAS-driven lung adenocarcinoma by degrading p16.

Lung cancer is a common type of cancer that represents a health problem worldwide; lung adenocarcinoma (LUAD) is a major subtype of lung cancer. Although several treatments for LUAD have been developed, the mortality rate remains high because of uncontrollable progression. Further biological and clinicopathological studies are therefore needed. Here, we investigated the role of family with sequence similarity 111 member B (FAM111B), which is highly expressed in papillary-predominant LUAD; however, its role in cancer is unclear. An immunohistochemical analysis confirmed that papillary-predominant adenocarcinomas exhibited higher expression of FAM111B, compared with lepidic-predominant adenocarcinomas. Additionally, FAM111B expression was significantly correlated with clinical progression. In vitro functional analyses using FAM111B-knockout cells demonstrated that FAM111B plays an important role in proliferation and cell cycle progression of KRAS-driven LUAD under serum-starvation conditions. Furthermore, FAM111B regulated cyclin D1-CDK4-dependent cell cycle progression by degradation of p16. In summary, we revealed the clinical importance of FAM111B in human tumor tissues, as well as its function as a degradative enzyme. Therefore, FAM111B has potential as a clinicopathological prognostic marker for LUAD.

Overexpressed FAM111B degrades GSDMA to promote esophageal cancer tumorigenesis and cisplatin resistance.

BACKGROUND: Chemotherapeutic agents such as cisplatin are commonly used in patients with clinically unresectable or recurrent esophageal cancer (ESCA). However, patients often develop resistance to cisplatin, which in turn leads to a poor prognosis. Studies have shown that FAM111B may be involved in the development of tumors as an oncogene or tumor suppressor gene. However, the pathological role and corresponding mechanism of FAM111B in ESCA are still unclear. METHODS: The GEPIA web tool, ENCORI Pan-Cancer Analysis Platform and UALCAN-TCGA database were used to study the expression of FAM111B in ESCA. CCK-8, angiogenesis, Transwell and xenograft assays were applied to explore the biological function of FAM111B in ESCA. Western blot, RT-qPCR, and RNA-seq analyses were applied to study the FAM111B/GSDMA axis in the progression of ESCA cells. CCK-8 and xenograft assays were used to study the role of the FAM111B/GSDMA axis in determining the sensitivity of ESCA to cisplatin. RESULTS: Our results demonstrated that FAM111B is highly expressed in ESCA tissues compared to normal tissues. We showed that FAM111B promotes the progression of ESCC cells by binding to GSDMA and that the trypsin protease domain is essential for the activity of FAM111B. Furthermore, we showed that the FAM111B/GSDMA axis regulates cisplatin sensitivity in ESCA. CONCLUSIONS: Overall, we identified a novel FAM111B/GSDMA axis regulating ESCA tumorigenesis and chemosensitivity, at least in ESCC cells.

FAM111B Acts as an Oncogene in Bladder Cancer.

Bladder cancer (BLCA) is a prevalent malignancy of the urinary system, associated with a high recurrence rate and poor prognosis. FAM111B, which encodes a protein containing a trypsin-like cysteine/serine peptidase domain, has been implicated in the progression of various human cancers; however, its involvement in BLCA remains unclear. In this study, we investigated the expression of FAM111B gene in tumor tissues compared to para-tumor tissues using immunohistochemistry and observed a significantly higher FAM111B gene expression in tumor tissues. Furthermore, analysis of clinical characteristics indicated that the increased FAM111B gene expression correlated with lymphatic metastasis and reduced overall survival. To investigate its functional role, we employed FAM111B-knockdown BLCA cell models and performed cell proliferation, wound-healing, transwell, and flow cytometry assays. The results showed that decreased FAM111B gene expression inhibited proliferation and migration but induced apoptosis in BLCA cells. In vivo experiments further validated that FAM111B knockdown suppressed tumor growth. Overall, our findings suggest that FAM111B acts as an oncogene in BLCA, playing a critical role in tumorigenesis, progression, and metastasis of BLCA. In conclusion, we have demonstrated a strong correlation between the expression of FAM111B gene and the development, progression, and metastasis of bladder cancer (BLCA). Thus, FAM111B is an oncogene associated with BLCA and holds promise as a molecular target for future treatment of this cancer.

FAM111B dysregulation promotes malignancy in fibrosarcoma and POIKTMP and a low-cost method for its mutation screening.

INTRODUCTION: Mutations in the uncharacterised human FAM111B gene are associated with POIKTMP, a rare multi-organ fibrosing disease. Recent studies also reported the overexpression of FAM111B in specific cancers. Moreover, FAM111B mutation screening may prove expensive in under-resourced facilities. Therefore, this study investigated its cellular function and dysfunction and described an inexpensive mutation screening method. MATERIALS AND METHODS: FAM111B expression was assessed in silico and validated in vitro in cell lines and primary skin fibroblasts from a South African POIKTMP-patient with the heterozygous FAM111B gene mutation: NM_198947.4: c.1861T>G (p. Tyr621Asp or Y621D) by qPCR and western blot. The cellular function of FAM111B was studied in HT1080 using various cell-based functional assays, and the Y621D mutation was genotyped by PCR-RFLP. RESULTS: Expression studies showed upregulated FAM111B mRNA and protein in the cancer cells. High FAM111B expression with robust nuclear localization occurred in HT1080. Additionally, expression data and cell-based assays indicated that FAM111B led to the upregulation of cell migration, decreased cell apoptosis, and modulatory effects on cell proliferation. Y621D mutation showed similar effects on cell migration but minimal impact on cell apoptosis. FAM111B mRNA and protein expression were markedly downregulated (p ≤ 0.05) in the POIKTMP-patient's fibroblasts. The PCR-RFLP method successfully genotyped Y621D gene mutation. DISCUSSION: FAM111B is a cancer-associated nuclear protein: Its modulation by mutations or overexpression may contribute to the malignancy of cancers and POIKTMP/fibrosis and poor clinical outcomes and represents a viable prognostic marker or therapeutic target. Furthermore, the PCR-RFLP method could prove a valuable tool for FAM111B mutation validation or screening in resource-constrained laboratories.

Pan-Cancer Analysis of the Tumorigenic Effect and Prognostic Diagnostic Value of FAM111B in Human Carcinomas.

Introduction: FAM111B (FAM111 trypsin-like peptidase B) gene mutations have been linked to a hereditary fibrosing poikiloderma disorder known to cause poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP). Overexpression of FAM111B has been associated with an increased risk of certain cancers with a poor prognosis, although the relationship between FAM111B and other tumors is still unclear, and the molecular mechanism of its action is not fully understood. Methods: We investigated the biological functions of FAM111B in 33 solid tumors using multi-omics data. We further recruited 109 gastric cancer (GC) patients for a clinical cohort study to confirm the effect of FAM111B on early tumor recurrence. Furthermore, we assessed the role of FAM111B in GC cell proliferation and migration via EdU incorporation, CCK8 and transwell assays in vitro. Results: We found that FAM111B can enhance oncogenesis and progression in multiple tumor types. The clinical cohort of GC showed that upregulation of FAM111B is associated with early recurrence of GC, and knockdown of the FAM111B gene can inhibit the proliferation and migration of GC cells. Gene enrichment analysis indicates that FAM111B promotes cancer through immune system process, chromosome instability, DNA repair, and apoptosis regulation. Mechanistically, FAM111B appears to promote the growth cycle of malignant tumor cells while inhibiting apoptosis. Conclusion: FAM111B may serve as a potential pan-cancer biomarker for predicting the prognosis and survival of malignant tumor patients. Our study elucidates the role of FAM111B in the occurrence and development of various cancers, and highlights the need for future research on FAM111B in cancers.

High FAM111B expression predicts aggressive clinicopathologic features and poor prognosis in ovarian cancer.

BACKGROUNDS: Ovarian cancer (OC) is the second most common gynecological tumor with the highest mortality rate worldwide. High FAM111B expression has been reported as a predictor of poor prognosis in other cancers, but its correlation with OC has not been reported. METHODS: Immunohistochemistry of tissue microarrays was performed to detect FAM111B expression levels in 141 OC patient tissues. The prognostic value of FAM111B was determined by Kaplan-Meier survival analysis, and correlations between FAM111B expression and clinicopathologic features were investigated by the Clu-square test. The significance of FAM111B expression was verified bioinformatically using the Gene Expression Omnibus database. Protein-protein interaction were performed to explore downstream mechanisms of FAM111B in OC. RESULTS: Among 141 OC patients, FAM111B was positively expressed in 87.23%, 58.16%, and 87.94%; and highly expressed in 8.51%, 17.02%, and 19.86%, as evaluated by cytoplasmic, nuclear, and combined cytoplasmic/nuclear staining. FAM111B expression was positively correlated with the expression of tumor protein markers KI67, EGFR, and PDL-1. Patients with high FAM111B expression had aggressive clinicopathologic features and shorter overall survival (P value 0.0428, 0.0050, 0.0029) and progression-free survival (P value 0.0251, 0.012, 0.0596) compared to the low FAM111B expression group for cytoplasmic, nuclear, and combined cytoplasmic/nuclear groups, respectively. These results were verified using patient data from the Gene Expression Omnibus. Seventeen genes co-expressed with FAM111B were primarily involved in "negative regulation of histone modification", "hippo signaling" and "inner ear receptor cell differentiation". CONCLUSIONS: High FAM111B expression may serve as a novel prognostic predictor and molecular therapeutic target for OC.

Silencing of FAM111B inhibited proliferation, migration and invasion of hepatoma cells through activating p53 pathway.

BACKGROUND: The function of Family with sequence similarity 111 member B (FAM111B) has been reported in multiple malignancies, but its involvement in occurrence and development of hepatocellular carcinoma (HCC) is still unclear. PURPOSE: To investigate the role of FAM111B in HCC and explore the potential molecular mechanism. METHODS: We examined the mRNA level of FAM111B via qPCR and protein level via immunohistochemistry in human HCC tissues. siRNA was used to construct a FAM111B-knockdown model in HCC cell lines. CCK-8, colony formation, transwell, and wound healing assays were performed to investigate the effect of FAM111B on proliferation, migration and invasion of HCC cell. Gene Set Enrichment Analysis, western blotting, and flow cytometry were carried out to find the related molecular mechanism. RESULTS: Human HCC tumor tissues exhibited higher expression of FAM111B, and high FAM111B expression was associated with poor prognosis. Vitro assays demonstrated that knockdown of FAM111B greatly repressed proliferation, migration and invasion of HCC cells. Furthermore, silencing of FAM111B significantly resulted in cell cycle arrest at G0/G1 and downregulation of epithelial-mesenchymal transition (EMT)-related proteins MMP7 and MMP9 via activation of p53 pathway. CONCLUSION: FAM111B played an essential role in promoting HCC development by regulation of p53 pathway.

Silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer.

Ovarian cancer is the most lethal gynecological tumor in women worldwide. FAM111B (family with sequence similarity 111 member B) is an oncoprotein associated with multiple cancers, but its biological functions in ovarian cancer remain elusive. In this study, FAM111B was overexpressed in ovarian cancer tissues and cell lines. Functional studies in vitro revealed that silencing of FAM111B inhibited ovarian cancer cell proliferation, invasion, and migration, as well as increased cell apoptosis. Furthermore, FAM111B silencing arrested the ovarian cancer cell cycle at the G1/S phase. Furthermore, western blot assays demonstrated that silencing of FAM111B resulted in downregulation of phospho-AKT (p-AKT) protein expression, as well as upregulation of p53 and caspase-1 protein expression. The xenograft animal model of ovarian cancer demonstrated that FAM111B silencing inhibited tumor growth, enhanced cell apoptosis, and inhibited Ki-67 and proliferating cell nuclear antigen (PCNA) protein expression in vivo. Conversely, the overexpression of FAM111B exhibited opposite effects on the ovarian cancer xenograft. It was previously established that inactivating AKT inhibited ovarian cancer progression. This study found that silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer. Caspase-1 and p53 signaling also influenced the function of FAM111B in SKOV3 cells. Collectively, our results demonstrate that silencing of FAM111B is a potential therapeutic strategy against ovarian cancer.

Loss of FAM111B protease mutated in hereditary fibrosing poikiloderma negatively regulates telomere length.

Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the FAM111B gene that encodes a nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterized the cellular roles of human FAM111B using U2OS and MCF7 cell lines and report here that the protease interacts with components of the nuclear pore complex. Loss of FAM111B expression resulted in abnormal nuclear shape and reduced telomeric DNA content suggesting that FAM111B protease is required for normal telomere length; we show that this function is independent of telomerase or recombination driven telomere extension. Even though FAM111B-deficient cells were proficient in DNA repair, they showed hallmarks of genomic instability such as increased levels of micronuclei and ultra-fine DNA bridges. When mutated as in HFP, FAM111B was more frequently localized to the nuclear envelope, suggesting that accumulation of the mutated protease at the nuclear periphery may drive the disease pathology.

Case report: Discovery of a de novo FAM111B pathogenic variant in a patient with an APECED-like clinical phenotype.

Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and poikiloderma in association with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) are rare inherited syndromes resulting from biallelic pathogenic variants in AIRE and heterozygous pathogenic variants in FAM111B, respectively. The clinical diagnosis of APECED and POIKTMP rely on the development of two or more characteristic disease manifestations that define the corresponding syndromes. We discuss the shared and distinct clinical, radiographic, and histological features between APECED and POIKTMP presented in our patient case and describe his treatment response to azathioprine for POIKTMP-associated hepatitis, myositis, and pneumonitis. Methods: Through informed consent and enrollment onto IRB-approved protocols (NCT01386437, NCT03206099) the patient underwent a comprehensive clinical evaluation at the NIH Clinical Center alongside exome sequencing, copy number variation analysis, autoantibody surveys, peripheral blood immunophenotyping, and salivary cytokine analyses. Results: We report the presentation and evaluation of a 9-year-old boy who was referred to the NIH Clinical Center with an APECED-like clinical phenotype that included the classic APECED dyad of CMC and hypoparathyroidism. He was found to meet clinical diagnostic criteria for POIKTMP featuring poikiloderma, tendon contractures, myopathy, and pneumonitis, and exome sequencing revealed a de novo c.1292T>C heterozygous pathogenic variant in FAM111B but no deleterious single nucleotide variants or copy number variants in AIRE. Discussion: This report expands upon the available genetic, clinical, autoantibody, immunological, and treatment response information on POIKTMP.

A Boolean model of the oncogene role of FAM111B in lung adenocarcinoma.

The ultimate goal of this study is to analyze the gene regulation between FAM111B and p53 in lung adenocarcinoma using Boolean networks. Recent studies have shown that downregulation of FAM111B enhances the G2/M cell cycle checkpoint in the respective cell lines. Upregulation of p53 directly downregulates FAM111B, which is directed to affect cell cycle controllers Cdc25C and Cdk1/CyclinB, thereby controlling G2/M cell cycle arrest. As for apoptosis, down-regulation of FAM111B by p53 directly regulates the BAG3/Bcl-2 axis, which triggers apoptotic cell death. However, the molecular mechanisms involving p53 and FAM111B in G2/M checkpoint regulation are still unknown. Thus, we present a Boolean model of the G2/M checkpoint considering the effect of p53 and FAM111B. Our model indicates that the cell fate between the two cellular phenotypes, arrest, and apoptosis, at the G2/M checkpoint is non-deterministic and is controlled by p53. The model was compared with the experimental data involving gain- or loss-of-function genes and achieved a fair agreement. The model predicts a positive circuit involving p53/FAM111B/BAG3. Our circuit perturbation analysis suggests that this circuit may be essential for controlling cell-fate decisions at the G2/M checkpoint. Our model supports that FAM111B is an engaging target for drug development in lung adenocarcinoma.

Proposed Cellular Function of the Human FAM111B Protein and Dysregulation in Fibrosis and Cancer.

FAM111B gene mutations are associated with a hereditary fibrosing poikiloderma known to cause poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP). In addition, the overexpression of FAM111B has been associated with cancer progression and poor prognosis. This review inferred the molecular function of this gene's protein product and mutational dysfunction in fibrosis and cancer based on recent findings from studies on this gene. In conclusion, FAM111B represents an uncharacterized protease involved in DNA repair, cell cycle regulation, and apoptosis. The dysregulation of this protein ultimately leads to fibrotic diseases like POIKTMP and cancers via the disruption of these cellular processes by the mutation of the FAM111B gene. Hence, it should be studied in the context of these diseases as a possible therapeutic target.