FAM84B Human

What is FAM84B and where is it located in the human genome?

FAM84B (also known as LRATD2) is located on chromosome 8q24.21, a region identified as a susceptibility locus for various cancer types. This gene is involved in the formation of DNA-repair complexes . The 8q24.21 locus represents one of the most amplified regions in several cancer types, particularly in ESCC, where FAM84B amplification occurs in 44% of cases according to genomic analyses .

Methodologically, researchers typically identify FAM84B using genomic techniques such as whole genome sequencing (WGS) and whole exome sequencing (WES), with copy number alterations analyzed through computational algorithms like GISTIC (Genomic Identification of Significant Targets in Cancer).

What is the association between FAM84B copy number amplification and cancer?

FAM84B copy number amplification (CNA) has been observed across multiple cancer types with significant clinical implications:

To investigate FAM84B CNAs, researchers employ techniques including:

• Whole genome/exome sequencing

• Copy number analysis algorithms

• Kaplan-Meier survival analysis

• Cox multivariate analysis for prognostic assessment

What cellular processes does FAM84B influence?

FAM84B influences several key cellular processes relevant to cancer development:

• Cell proliferation: Knockdown of FAM84B decreases cell proliferation in ESCC and PDAC cell lines, while overexpression enhances growth both in vitro and in vivo .

• Cell cycle regulation: FAM84B knockdown arrests cells in the G1/S phase as demonstrated by flow cytometry studies .

• Apoptosis: FAM84B knockdown induces apoptosis in cancer cells, particularly in PDAC models .

• Cellular metabolism: FAM84B affects mitochondrial function and glycolysis in PDAC cells, supporting the metabolic demands of proliferating cancer cells .

• Cell invasion and metastasis: FAM84B overexpression enhances invasion in prostate cancer cells and promotes lung metastasis in tail-vein mouse models .

RNA sequencing analysis of FAM84B-overexpressing tumors has revealed differentially expressed genes affecting cell cycle progression, Golgi to ER processes, mitochondrial events, and translation regulation .

How does FAM84B expression vary between normal and cancer tissues?

Immunohistochemistry analysis of FAM84B in 104 primary ESCC samples demonstrated markedly higher expression in tumors compared to matched normal tissues . A positive correlation exists between FAM84B copy number amplification and mRNA expression levels in both TCGA ESCC cohort (r = 0.3296; P = 0.0011; n = 95) and a 155 RNA-seq ESCC cohort (r = 0.449, P < 0.001; n = 155) .

In prostate cancer, FAM84B expression follows a progressive increase pattern:

• Elevated in primary tumors (n = 343) compared to normal tissue (n = 181)

• Further increased in metastatic samples

• Higher in prostate cancer stem cell-generated xenografts than non-stem cell xenografts

• Elevated in lung metastasis compared to subcutaneous xenografts

This expression pattern suggests FAM84B upregulation is associated with cancer progression and aggressive phenotypes across multiple cancer types.

Which cancer types have been associated with FAM84B dysregulation?

Several specific cancer types have been associated with FAM84B dysregulation:

• Esophageal squamous cell carcinoma (ESCC)

• Prostate cancer (PC)

• Pancreatic ductal adenocarcinoma (PDAC)

• Breast cancer

• Glioma

• Colon cancer

Pan-cancer analysis revealed that 28 out of 32 tumor types displayed amplification of FAM84B to various degrees , suggesting its dysregulation may be relevant to a broad spectrum of human malignancies.

What are the molecular mechanisms through which FAM84B promotes tumorigenesis?

FAM84B promotes tumorigenesis through multiple molecular mechanisms that vary by cancer type:

In ESCC:

• FAM84B interacts with the C-terminal domain (189-294aa) of Nucleophosmin 1 (NPM1)

• This interaction increases NPM1 nuclear expression

• Elevated nuclear NPM1 inhibits CDKN2A (p16) protein expression

• Reduced CDKN2A allows accelerated cell cycle progression, particularly at the G1/S transition

In prostate cancer:

• FAM84B overexpression leads to increased AKT activation

• It reduces BAD (BCL2 associated agonist of cell death) expression

• RNA-seq analysis revealed numerous differentially expressed genes affecting cell cycle progression, Golgi to ER processes, and mitochondrial events

In PDAC:

• FAM84B affects the Wnt/β-catenin pathway

• It increases nuclear accumulation of β-catenin

• This leads to altered expression of c-Myc and lactate dehydrogenase A

• FAM84B enhances aerobic glycolysis and mitochondrial function

These diverse mechanisms highlight FAM84B's role as a multifunctional oncogene affecting key cancer-related pathways across different tumor types.

How does FAM84B interact with the NPM1 protein and what are the functional consequences?

FAM84B directly interacts with NPM1 (Nucleophosmin 1), specifically targeting its C-terminal domain (189-294aa). Co-immunoprecipitation (Co-IP) assays revealed that FLAG-tagged FAM84B bound to NPM1-118-294aa and full-length NPM1, but not to NPM1-1-117aa, NPM1-118-188aa, or NPM1-1-188aa fragments .

This interaction produces several functional consequences:

• Increased nuclear localization of NPM1: Nucleoplasmic separation assays demonstrated that FAM84B overexpression increased nuclear localization and expression of both FAM84B and NPM1 .

• Dose-dependent increase in NPM1 levels: Ectopic expression of FAM84B increased NPM1 levels in a dose-dependent manner .

• Inhibition of CDKN2A (p16) expression: NPM1 overexpression inhibited CDKN2A protein expression .

• Cell cycle acceleration: The suppression of CDKN2A, a key cell cycle inhibitor, results in accelerated cell cycle progression, particularly at the G1/S checkpoint .

This FAM84B-NPM1-CDKN2A axis represents a novel mechanism through which FAM84B amplification contributes to tumorigenesis in ESCC.

What is the relationship between FAM84B and the Wnt/β-catenin pathway in cancer?

FAM84B interacts with the Wnt/β-catenin pathway across multiple cancer types:

In PDAC:

• Knockdown of FAM84B decreased nuclear accumulation of β-catenin

• FAM84B knockdown decreased expression of c-Myc and lactate dehydrogenase A (LDHA), both downstream targets of Wnt/β-catenin

• The effects of FAM84B overexpression on cell proliferation, apoptosis, metabolism, and glycolysis were blocked by XAV939, a specific Wnt/β-catenin pathway inhibitor

In other cancers:

• FAM84B promotes tumorigenesis through the Wnt/β-catenin pathway in pancreatic ductal adenocarcinoma

• In glioma, FAM84B affects the Akt/GSK-3β/β-catenin pathway

This consistent relationship across multiple cancer types suggests that modulation of Wnt/β-catenin signaling may be a conserved mechanism through which FAM84B exerts its oncogenic effects.

How does FAM84B affect cellular metabolism and glycolysis in cancer cells?

FAM84B significantly impacts cellular metabolism, particularly in pancreatic ductal adenocarcinoma (PDAC):

• Regulation of glycolysis: FAM84B knockdown suppressed glycolysis in PDAC cells, while overexpression enhanced it, promoting the Warburg effect characteristic of many cancer cells .

• Influence on mitochondrial function: Experimental studies demonstrated that FAM84B affects mitochondrial function in PDAC cells. Knockdown suppressed mitochondrial function, while overexpression enhanced it .

• Modulation of metabolic enzymes: FAM84B alters the expression of key metabolic enzymes, particularly lactate dehydrogenase A (LDHA), which catalyzes the conversion of pyruvate to lactate in the final step of glycolysis .

• Wnt/β-catenin pathway involvement: The metabolic effects of FAM84B are mediated, at least in part, through the Wnt/β-catenin pathway, as treatment with the Wnt/β-catenin inhibitor XAV939 blocked the metabolic changes induced by FAM84B overexpression .

These metabolic alterations likely contribute to FAM84B's ability to promote cancer cell proliferation and survival by providing energy and biosynthetic precursors needed for rapid cell division.

What experimental approaches are most effective for studying FAM84B function in cancer models?

Based on the search results, several complementary experimental approaches have proven effective for studying FAM84B:

• Genetic manipulation in cell lines:

  • Knockdown using shRNA or siRNA (applied in ESCC, PDAC, and prostate cancer cell lines)

  • Overexpression using expression vectors

  • CRISPR-Cas9 gene editing for complete knockout

• In vivo models:

  • Subcutaneous xenograft tumor models using FAM84B-manipulated cancer cells

  • Tail-vein injection models to study metastasis (particularly in prostate cancer studies)

  • Genetically engineered mouse models

• Protein interaction studies:

  • Co-immunoprecipitation (Co-IP) to identify protein binding partners (e.g., NPM1)

  • Domain mapping using truncated protein constructs

  • Nucleoplasmic separation assay to study protein localization changes

• Functional assays:

  • Cell proliferation assays (MTT, BrdU incorporation)

  • Flow cytometry for cell cycle analysis and apoptosis detection

  • Invasion and migration assays

  • Metabolic assays for glycolysis and mitochondrial function

• Clinical correlation:

  • Analysis of FAM84B copy number amplification in patient cohorts

  • Correlation with clinical features and outcomes

  • Immunohistochemistry for protein expression in patient samples

These approaches, especially when combined, provide comprehensive insights into FAM84B function and its role in cancer.

How does FAM84B amplification affect patient prognosis across different cancer types?

FAM84B amplification consistently associates with worse patient prognosis across multiple cancer types:

In ESCC:

In PDAC:

In Prostate Cancer:

• Amplification occurred more frequently in metastatic castration-resistant prostate cancer (26%) compared to primary prostate cancers (4.8%, p < 0.0001)

• The amplification was associated with reductions in disease-free survival

In Pan-Cancer Analysis:

These findings establish FAM84B amplification as a negative prognostic factor across diverse cancer types.

What is the potential of FAM84B as a therapeutic target in cancer treatment?

FAM84B shows considerable potential as a therapeutic target based on several lines of evidence:

• Oncogenic function: FAM84B promotes cell proliferation, invasion, tumor growth, and metastasis across multiple cancer types. Inhibiting FAM84B function could potentially reverse these oncogenic effects .

• Frequent alteration in cancer: FAM84B amplification occurs in multiple cancer types, with higher frequency in advanced and metastatic disease, suggesting relevance particularly for aggressive cancers .

• Impact on treatment response: PDAC cells with lower expression of FAM84B were more sensitive to gemcitabine-induced cell proliferation inhibition both in vitro and in vivo .

• Selective expression: FAM84B shows higher expression in cancer tissues compared to normal tissues, potentially providing a therapeutic window for targeting cancer cells while sparing normal cells .

• Defined molecular interactions: The identification of specific protein interactions (e.g., with NPM1) and pathway involvement (e.g., Wnt/β-catenin) provides potential for developing targeted therapies that disrupt these interactions .

Multiple studies conclude that FAM84B may be not only a novel diagnostic marker but also a promising therapeutic target for various cancer types .

How does FAM84B expression influence response to chemotherapy?

The search results provide specific information about FAM84B's influence on chemotherapy response in pancreatic ductal adenocarcinoma (PDAC):

PDAC cells with lower expression of FAM84B were found to be more sensitive to gemcitabine-induced cell proliferation inhibition both in vitro and in vivo . This suggests that FAM84B expression may confer resistance to gemcitabine, a standard chemotherapeutic agent used in PDAC treatment.

Several potential mechanisms may explain this relationship:

• Cell cycle effects: FAM84B promotes cell cycle progression, particularly at the G1/S phase. Gemcitabine efficacy may be affected by FAM84B's influence on cell cycle dynamics .

• Apoptosis regulation: FAM84B has anti-apoptotic effects, potentially through activation of AKT and reduction of BAD expression. This could counteract the pro-apoptotic effects of chemotherapy .

• Metabolic reprogramming: FAM84B enhances glycolysis and mitochondrial function, which could provide cancer cells with metabolic adaptations that help them survive chemotherapy exposure .

• Wnt/β-catenin pathway activation: FAM84B activates the Wnt/β-catenin pathway, which has been implicated in chemoresistance in various cancer types .

These findings suggest FAM84B expression status might predict chemotherapy response and that inhibiting FAM84B might potentiate chemotherapy effects.

What signaling pathways downstream of FAM84B contribute to cancer progression?

Several key signaling pathways downstream of FAM84B contribute to cancer progression:

• NPM1-CDKN2A axis in ESCC:

  • FAM84B binds to the C-terminal domain of NPM1

  • This increases NPM1 nuclear expression

  • Nuclear NPM1 inhibits CDKN2A (p16) expression

  • Reduced CDKN2A allows accelerated cell cycle progression

• Wnt/β-catenin pathway in PDAC and other cancers:

  • FAM84B increases nuclear accumulation of β-catenin

  • This alters expression of downstream targets like c-Myc and LDHA

  • Inhibition of Wnt/β-catenin with XAV939 blocks FAM84B's effects

• AKT/BAD pathway in prostate cancer:

  • FAM84B overexpression enhances AKT activation

  • This reduces expression of BAD (BCL2 associated agonist of cell death)

• Akt/GSK-3β/β-catenin pathway in glioma

• Cell cycle regulation:

  • FAM84B affects cell cycle progression, particularly at the G1/S checkpoint

  • Knockdown of FAM84B arrests cells in G1/S phase

• Metabolic pathways:

  • FAM84B regulates glycolysis and mitochondrial function

  • It affects expression of metabolic enzymes like LDHA

These diverse downstream pathways illustrate the multifaceted mechanisms through which FAM84B drives cancer progression across different tumor types.

How can FAM84B expression or amplification be used as a biomarker in clinical settings?

FAM84B shows significant potential as a clinical biomarker:

The consistent association between FAM84B alterations and clinical outcomes across multiple cancer types suggests its value for patient stratification, treatment planning, and prognosis estimation.