Targeting of tumoral NAC1 mitigates myeloid-derived suppressor cell-mediated immunosuppression and potentiates anti-PD-1 therapy in ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade (ICB) therapy. Here, we report that nucleus accumbens-associated protein 1 (NAC1), a putative driver of EOC, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME), led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression.

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis.

Co-Targeting Nucleus Accumbens Associate 1 and NF-κB Signaling Synergistically Inhibits Melanoma Growth.

Nucleus-accumbens-associated protein-1 (NAC1) is a cancer-related transcriptional factor encoded by the gene, which is amplified and overexpressed in various human cancers and has been appreciated as one of the top potential cancer driver genes. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. Here, we show that NAC1 is a negative regulator of NF-κB signaling, and NAC1 depletion enhances the level of the nuclear NF-κB in human melanoma.

NAC1 confines virus-specific memory formation of CD4 T cells through the ROCK1-mediated pathway.

Nucleus accumbens-associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8 T cells, and antitumor immunity, but little is known about its effects on T-cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4 T cells during viral infection. Analysis of CD4 T cells from wild-type (WT) and NAC1-deficient ( ) mice showed that NAC1 is essential for T-cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4 T-cell survival in vitro.

Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression.

Mechanistic insights of NAC1 nuclear export and its role in ovarian cancer resistance to docetaxel.

In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel.

Expression of nucleus accumbens-1 in colon cancer negatively modulates antitumor immunity.

Background: Nucleus accumbens-1 (NAC-1) is highly expressed in a variety of tumors, including colon cancer, and is closely associated with tumor recurrence, metastasis, and invasion.

Aim: To determine whether and how NAC-1 affects antitumor immunity in colon cancer.

Methods: NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression; tumor cells with or without knockdown of NAC-1 were treated with CD8 T cells to test their cytocidal effect.

Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion.

Background: T cell-mediated antitumor immunity has a vital role in cancer prevention and treatment; however, the immune-suppressive tumor microenvironment (TME) constitutes a significant contributor to immune evasion that weakens antitumor immunity. Here, we explore the relationship between nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB (broad-complex, Tramtrack, bric a brac)/POZ (Poxvirus, and Zinc finger) gene family, and the TME.

Methods: Adoptive cell transfer (ACT) of mouse or human tumor antigen (Ag)-specific CD8 cytotoxic T lymphocytes (CTLs) was tested in an immunocompetent or immunodeficient mouse model of melanoma with or without expression of NAC1.

Expression of NAC1 Restrains the Memory Formation of CD8 T Cells during Viral Infection.

Nucleus accumbens-associated protein 1 (NAC1) is a transcription co-factor that has been shown to possess multiple roles in stem cell and cancer biology. However, little is known about its roles in regulation of the immune system. In the current study, we observed that expression of NAC1 impacted the survival of CD8 T cells in vitro.

NAC1 modulates autoimmunity by suppressing regulatory T cell-mediated tolerance.

We report here that nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the Broad-complex, Tramtrack, Bric-a-brac/poxvirus and zinc finger (BTB/POZ) gene family, is a negative regulator of FoxP3 in regulatory T cells (T) and a critical determinant of immune tolerance. Phenotypically, NAC1 mice showed substantial tolerance to the induction of autoimmunity and generated a larger amount of CD4 T that exhibit a higher metabolic profile and immune-suppressive activity, increased acetylation and expression of FoxP3, and slower turnover of this transcription factor. Treatment of T with the proinflammatory cytokines interleukin-1β or tumor necrosis factor-α induced a robust up-regulation of NAC1 but evident down-regulation of FoxP3 as well as the acetylated FoxP3.

eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma.

Background: Immune checkpoint blockade (ICB) targeting programmed death ligand-1 (PD-L1)/programmed cell death protein-1 (PD-1) pathway has become an attractive strategy for cancer treatment; however, unsatisfactory efficacy has limited its clinical benefits. Therefore, a more comprehensive understanding of the regulation of PD-L1 expression is essential for developing more effective cancer immunotherapy. Recent studies have revealed the important roles of eukaryotic elongation factor 2 kinase (eEF2K) in promoting epithelial-mesenchymal transition (EMT), angiogenesis, tumor cell migration and invasion; nevertheless, the exact role of eEF2K in the regulation of tumor immune microenvironment (TIME) remains largely unknown.

Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8 T cells.

eEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8 T cells. CD8 T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion.

Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase.

Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth. As a structurally unique member of the alpha-kinase family, eEF2K is essential to cell survival under stressful conditions, as it contributes to both cell viability and proliferation. Known as the modulator of the global rate of protein translation, eEF2K inhibits eEF2 (eukaryotic Elongation Factor 2) and decreases translation elongation when active.

Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance.

Immunotherapies such as CAR-T cell transfer and antibody-targeted therapy have produced promising clinical outcomes in patients with advanced and metastatic cancer that are resistant to conventional therapies. However, with increasing use of cancer immunotherapy in clinical treatment, multiple therapy-resistance mechanisms have gradually emerged. The tumor microenvironment (TME), an integral component of cancer, can significantly influence the therapeutic response.

Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy.

Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy.

RSK2 protects human breast cancer cells under endoplasmic reticulum stress through activating AMPKα2-mediated autophagy.

Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells.

Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HBV Replication through Production of IFN-γ and TNF-⍺.

The viral antigen (Ag)-specific CD8 cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress hepatitis B virus (HBV) infection.

UCH-L1-mediated Down-regulation of Estrogen Receptor α Contributes to Insensitivity to Endocrine Therapy for Breast Cancer.

: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. : Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases.

Heat Shock Proteins in Cancer Immunotherapy.

Heat shock proteins (HSPs) are highly conserved molecular chaperones with divergent roles in various cellular processes. The HSPs are classified according to their molecular size as HSP27, HSP40, HSP60, HSP70, and HSP90. The HSPs prevent nonspecific cellular aggregation of proteins by maintaining their native folding energetics.

Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents.

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive.

Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes.

The autoantigen-specific Tregs from pluripotent stem cells (PSCs), i.e., PSC-Tregs, have the ability to suppress autoimmunity.

Protective Cancer Vaccine Using Genetically Modified Hematopoietic Stem Cells.

Hematopoietic stem cells (HSCs) yield both the myeloid and lymphoid lineages of blood cells and can be reprogrammed into tumor antigen (Ag)-specific CD8⁺ cytotoxic T lymphocytes (CTLs) to prevent tumor growth. However, the optimal approach for differentiating tumor Ag-specific CTLs from HSCs, such as HSC-CTLs, remains elusive. In the current study, we showed that a combination of genetic modification of HSCs and in vivo T cell development facilitates the generation of Ag-specific CTLs that suppressed tumor growth.

Correction: Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia.

[This corrects the article DOI: 10.18632/oncotarget.9717.

eEF-2 Kinase-targeted miR-449b confers radiation sensitivity to cancer cells.

The roles of microRNA in regulation of various biological processes and in modulation of therapeutic effects have been widely appreciated. In this study, we found a positive correlation between miR-449 b expression and radiation sensitivity in cancer cells and in tumor specimens from patients. We showed that eEF-2 kinase, a negative regulator of global protein synthesis, is a target of miR-449 b.