Table 2 Functional roles of FADD in different types of cancer

BC

High expression or amplification of FADD was negatively associated with the abundance of CD4 + T cells and dendritic cell infiltration in BC (p < 0.05). High expression of FADD mRNA significantly associated with RFS BC in patients (p < 0.05). High expression of FADD was frequently detected in luminal B and high-grade BC with shorter metastasis-free survival times (p < 0.05).

Zhou et al. (Zhou et al. 2022a)

Increase copy number and mRNA overexpression of FADD are frequently observed in primary BC.

Callegari et al. (Callegari et al. 2016)

FADD knockdown promoted autophagy of BC cells by downregulating Rheb and inhibiting mTORC1 activity.

He et al. (He et al. 2016)

FADD expression was significantly associated with T stage (P = 0.046). The combination of FADD, PPFIA1, and TMEM16A genes was significantly correlated with perineural invasion (p = 0.022) and DFS (p = 0.034).

Choi et al. (Choi et al. 2014)

MKRN1 mediated the ubiquitination and proteasomal degradation of FADD. The stabilization of FADD facilitated extrinsic apoptosis by promoting caspase-8 and caspase-3 cleavage in BC cells. FADD participated in the modulation of necroptosis upon caspase inhibition.

Lee et al. (Lee et al. 2012a)

JNK-mediated phosphorylation of FADD inhibited cell growth and metastasis through G2/M arrest.

Matsuyoshi et al. (Matsuyoshi et al. 2006)

GC

FADD was negatively regulated by miR-633, and its upregulation enhanced DOX/DDP induced apoptosis in GC cells.

Pang et al. (Pang et al. 2019)

FADD expression was negatively associated with H19 and miR-675 expression in GC. FADD mediated the promotion of H19/miR-675 axis on GC progression.

Yan et al. (Yan et al. 2017)

The expression of p-FADD in GC was heterogenous in its location, whereas its expression in normal gastric cells was uniform nuclear expression.

Yoo et al. (Yoo et al. 2007)

NSCLC

NSCLC patients with overexpression of FADD had lower OS rates (p = 0.033). The upregulation of FADD was an independent poor prognostic biomarker for patients with surgically resected NSCLC (p = 0.027).

Chen et al. (Chen et al. 2021)

High FADD expression predicted poor prognosis of NSCLC patients. The ubiquitin ligase SPOP promoted FADD degradation by directly binding to it. FADD mediated the inhibition of SPOP on NF-κB activity and its target genes expression.

Luo et al. (Luo et al. 2018)

FADD was specifically downregulated in NSCLC cells, and FADD loss was significantly associated with the presence of extracellular FADD. NSCLC tissues released significantly more FADD than non-tumoral tissue (P = 0.000003). The release of FADD increased significantly with the cancer stage, and was associated with both early and late steps of the metastasis process.

Cimino et al. (Cimino et al. 2012)

PCa

PCa patients with a greater positive p-FADD rate had a significantly lower biochemical recurrence rate than those with a lower positive p-FADD rate (p < 0.001). The positive p-FADD rate was negatively associated with Gleason score.

Ikeda et al. (Ikeda et al. 2013)

The overexpression of dephosphorylated FADD (S194A) promoted proliferation and invasion of PCa cells by enhancing hTERT expression and telomerase activity. PCa patients expressing low levels of p-FADD had significantly higher rates of biochemical recurrence than those with high p-FADD expression (p < 0.001).

Matsumura et al. (Matsumura et al. 2009)

The overexpression of phosphorylated FADD resulted in G2/M cell-cycle arrest, whereas the non-phosphorylated FADD overexpression resulted in cell cycle progression and enhanced colony-forming activity in PCa cells.

Shimada et al. (Shimada et al. 2005)

FADD was phosphorylated by JNK at Ser194 in PCa cells treated with PTX. Phosphorylated FADD enhanced the synergistic effects of paclitaxel on anticancer drug-induced apoptosis in PCa cells.

Shimada et al. (Shimada et al. 2004)

FADD mediated the effect of PTEN in promoting drug-induced apoptosis by facilitating caspase-8 activation and BID cleavage in PCa.

Yuan et al. (Yuan and Whang 2002)

Leukemia

FADD knockdown in Jurkat cells significantly inhibited cell proliferation, enhanced sensitivity to Etoposide-induced intrinsic apoptosis and resistance to TRAIL-induced extrinsic apoptosis by triggering a metabolic shift from glycolysis to mitochondrial respiration.

Zhou et al. (Zhou et al. 2022b)

FADD knockdown in Jurkat cells enhanced drug resistance, which could be partially overcome by induction of RIP1-dependent necroptosis through TNFR1 activation using combined treatment with TNFα and LCL161.

Mrkvova et al. (Mrkvova et al. 2021)

S194-P-FADD was more stable and preferentially localized to the cell nucleus, thereby promoting proliferation in T-cell lymphoblastic lymphoma cells. FADD phosphorylation was a prognostic biomarker in T-cell lymphoblastic lymphoma.

Marin-Rubio et al. (Marin-Rubio et al. 2019a)

The availability of FADD in the cytoplasm reduced in T-cell lymphoblastic lymphoma cells. Reduction of FADD phosphorylation that inversely correlates with the proliferation capacity and tumor aggressiveness. The reduction of FADD phosphorylation was negatively associated with the proliferation capacity and tumor aggressiveness.

Marin-Rubio et al. (Marin-Rubio et al. 2016)

FADD was a direct target of miR-128a. FADD downregulation by miR-128a conferred Fas-resistance on Jurkat cells. FADD upregulation induced by miR-128a knockdown sensitized Jurkat/R cells to the Fas-mediated apoptosis.

Yamada et al. (Yamada et al. 2014)

Glioma

FADD was downregulated by ATRX via the H3K27me3 enrichment, resulting in the enhancement of PARP1 stabilization in TMZ resistant glioma cells.

Han et al. (Han et al. 2020)

FADD overexpression induced apoptosis in about 85% of malignant glioma cells. The retroviral transfer of FADD gene significantly suppressed survival in malignant glioma cells by induction of apoptosis.

Kondo et al. (Kondo et al. 1998)

GBM

FADD overexpression inhibited proliferation and induced apoptosis in human GBM cells.

Wang et al. (Wang et al. 2017)

HCC

FADD mediated the role of OTULIN in preventing the development of chronic liver inflammation and HCC.

Verboom et al. (Verboom et al. 2020)

FADD mediated the apoptosis of hepatocytes, thereby promoting the development of hepatitis and HCC in NEMO(LPC-KO) mice

Ehlken et al. (Ehlken et al. 2014)

FADD mediated the role of truncated RIP3 (aa 224–518) in inducing apoptosis in human hepatocellular carcinoma cells QGY-7703.

Feng et al. (Feng et al. 2006)

FADD expression was significantly correlated with cell apoptosis in HCC (p < 0.05). The positive rate of FADD expression in HCC is lower than that in adjacent normal tissues (p < 0.05).

Sun et al. (Sun et al. 2000)

Melanoma

The degradation of FADD was inhibited by ADT-OH via downregulating MKRN1. The tumor-specific delivery of FADD combined with low-dose ADT-OH administration significantly suppressed tumor growth and induced cell apoptosis in melanoma.

Cai et al. (Cai et al. 2020)

The overexpression of FADD or truncated FADD (1-181 aa) induced apoptosis in B16F10 cells, The truncated FADD exhibited a more potent apoptotic effect than FADD. The tumor-targeted delivery of FADD or truncated FADD inhibited tumor growth by inducing apoptosis of tumor cells via activating caspase-dependent apoptotic pathway.

Yang et al. (Yang et al. 2016)

FADD decreased FAK expression by upregulating miR-7a, thereby promoting cell migration in melanoma.

Liu et al. (Liu et al. 2016)

OC

FADD mediated the induction of apoptosis by certain chemotherapeutic drugs in OC cells.

Milner et al. (Milner et al. 2002)

CRC

Phosphorylated FADD interacted with MT2A and co-localized with MT2A mostly to nuclei and slightly to cytoplasm. The co-expression of Phosphorylated FADD and MT2A inhibited the apoptosis and promote proliferation in CRC cells.

Marikar et al. (Marikar et al. 2016)

The overexpression of FADD mediated by adenovirus inhibited cell growth and enhanced apoptosis of SW480 cells and suppress growth of xenografts in mice.

He et al. (He et al. 2018)

FADD mediated apoptosis of CRC cells synergistically induced by Smac mimetic and DOX.

Yang et al. (Yang et al. 2020b)

Apigenin upregulated FADD and induced its phosphorylation, which may resulted in cell apoptosis and inhibition of tumor growth in CRC.

Wang et al. (Wang et al. 2011b)

FADD overexpression enhanced 5-FU sensitivity in CRC mice model. Stable overexpression of FADD significantly improved apoptosis-inducing effects of 5-FU on CRC cells.

Yin et al. (Yin et al. 2010)

HNSCC

The immunohistochemical overexpression of FADD was significantly associated with worse OS (p < 0.001), DSS (p < 0.001), DFS ((p < 0.001), higher clinical stage (p = 0.005), and a large magnitude of effect with N + status (p < 0.001).

Gonzalez-Moles et al. (Gonzalez-Moles et al. 2020)

High FADD expression was significantly associated with an increased rate of lymph node metastasis (p = 0.001), a shorter distant metastasis-free interval (p = 0.046).

Pattje et al. (Pattje et al. 2013)

HNSCC patients with tumors that were strongly positive for cyclin D1 and FADD had reduced OS (p = 0.003 and p < 0.001), DSS (p = 0.039 and p < 0.001), and DFS (p = 0.026 and p < 0.001), respectively. FADD was a significant independent predictor of DSS and DFS.

Rasamny et al. (Rasamny et al. 2012)

OSCC

FADD gene copy number and protein expression are potential prognostic biomarkers and are closely associated with lymph node metastasis in OSCC patients (p < 0.001).

Chien et al. ((Chien et al. 2016)

Clear cell renal cell carcinoma

FADD was downregulated in clear cell renal cell carcinoma compared with that in normal tissues. FADD-mediated apoptosis may suppress carcinogenesis in clear cell renal cell carcinoma.

Xu et al. (Xu et al. 2009)

PC

FADD is required for PC cell proliferation and that it is overexpressed to varying degrees in a variety of PC cell types. FADD protected PC cells from drug-induced apoptosis, whereas FADD knockdown enhanced the sensitivity of drug-resistant cells to ADR-mediated apoptosis.

Zhang et al. (Zhang et al. 2017)