The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

Abstract

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among or defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent inhibition of DNA synthesis, widespread binding of p53, and induction of target genes and p53-dependent cell cycle arrest and DNA damage sensitization. Cell cycle arrest induced by v2 silencing requires p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 promotes human cancer by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression. Cell Death and Differentiation (2017) 24, 181-191; doi:10.1038/cdd.2016 published online 11 November 2016 Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is the founding member of a recently described family of environmental stress response genes that are induced by TNFα. TNFAIP8 has been shown to promote or inhibit apoptosis, depending on cell type and context. 1,2 Although little is known about TNFAIP8, it has recently been found to be overexpressed in a wide range of human cancers. Some studies have suggested protumor functions for TNFAIP8, including enhancement of cell survival, proliferation, and metastasis [3][4][5][6][7][8][9] and resistance to cancer chemotherapeutics in mice. 4,10Nonetheless, nothing is known about how TNFAIP8 influences responses to DNA damage in cancer cells. Moreover, several transcript variants from the TNFAIP8 gene were recently registered in the NCBI reference sequence database, but no study to date has differentiated among them or defined the factors that govern their expression.The tumor suppressor p53 is a transcription factor that regulates many biological processes through its target gene network. Some of the well-characterized p53 target genes including p21/CDKN1A, growth arrest and DNA damageinducible 45a (GADD45A) and Bcl-2-like protein 4 (BAX) together promote senescence, cell cycle arrest, and apoptosis, all of which may contribute to the tumor suppressing functions of p53. 11,12Additional noncanonical tumorsuppressive pathways from p53 have recently been identified. [13][14][15] Improved characterization of the p53 DNAbinding sequence with modern sequencing techniques has led to the identification of a rapidly expanding list of p53 target genes. [16][17][18] Continued identification of these genes and characterization of their mechanisms of regulation and function will be critical to a full understanding of p53 and for full realization of opportunities to intervene upon p53 in cancer.Here, we identify ...

TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation

“…1c, d). Involvement of TNFAIP8 variant 2 in lung cancer development and progression has been reported earlier 23 . The expression of TNFAIP8 variant 1 was detected in HepG2 and Hep3B cells but not in SK-Hep1 cells, and isoforms three, four, and five were not detected in any of the cell lines (Supplementary Fig.…”

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations

“…In addition, we unveiled multiple, putatively unreported DA-CNVRs that map to relevant candidate genes (Table 1). Among those are several well-established drug targets and others in development, including but not limited to TNFAIP8, HSPA9, SLIT3, HCN2, GRK6, ITGB8, ADK, CD44, NR1D1, and SLC38A10 [30][31][32][33][34][35][36][37][38][39][40][41][42][43] . We performed similar enrichment analyses across each set of the domain-specific DA-CNVRs, showing that a number of the functional and genomic elements were enrichments in multiple disease domains ( Supplementary Fig.…”

Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non–Small Cell Lung Cancer Cells

“…activity (14). Furthermore, TNFAIP8 is critical for evasion of drug-induced apoptosis in lung tumor cells expressing mutant or wild-type P53 (21,22). Thus, TNFAIP8 is a prosurvival molecule along the TNFa/NF-kB axis.…”

“…21). TNFAIP8 broadly represses wild-type p53 in A549 lung cancer cells, and silencing of TNFAIP8 leads to enhanced p53 binding and induction of target gene expression, p53-dependent cell-cycle arrest, and apoptosis in doxorubicintreated lung cancer cells (22). Expression of transcriptional coactivator and a Hippo pathway effector YAP1 has been associated with resistance to TKI and BRAF inhibitors, upregulation of PD-L1, and poor survival in NSCLC (23,24).…”