Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons.

Immunotherapy has become established as major treatment modality for multiple types of solid tumors, including colorectal cancer. Identifying novel immunotherapeutic targets to enhance anti-tumor immunity and sensitize current immune checkpoint blockade (ICB) in colorectal cancer is needed. Here we report the histone demethylase PHD finger protein 8 (PHF8, KDM7B), a Jumonji C domain-containing protein that erases repressive histone methyl marks, as an essential mediator of immune escape. Ablation the function of PHF8 abrogates tumor growth, activates anti-tumor immune memory, and augments sensitivity to ICB therapy in mouse models of colorectal cancer. Strikingly, tumor PHF8 deletion stimulates a viral mimicry response in colorectal cancer cells, where the depletion of key components of endogenous nucleic acid sensing diminishes PHF8 loss-meditated antiviral immune responses and anti-tumor effects in vivo. Mechanistically, PHF8 inhibition elicits H3K9me3-dependent retrotransposon activation by promoting proteasomal degradation of the H3K9 methyltransferase SETDB1 in a demethylase-independent manner. Moreover, PHF8 expression is anti-correlated with canonical immune signatures and antiviral immune responses in human colorectal adenocarcinoma. Overall, our study establishes PHF8 as an epigenetic checkpoint, and targeting PHF8 is a promising viral mimicry-inducing approach to enhance intrinsic anti-tumor immunity or to conquer immune resistance.

The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress.

Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, the clinical benefits are often countered by a rapid tumor adaptive response. Here, we report that the oncoprotein B cell lymphoma 6 (BCL6) is a core component that confers solid tumor adaptive resistance to genotoxic stress. Multiple genotoxic agents promoted BCL6 transactivation, which was positively correlated with a weakened therapeutic efficacy and a worse clinical outcome. Mechanistically, we discovered that treatment with the genotoxic agent etoposide led to the transcriptional reprogramming of multiple pro-inflammatory cytokines, among which the interferon-α and interferon-γ responses were substantially enriched in resistant cells. Our results further revealed that the activation of interferon/signal transducer and activator of transcription 1 axis directly upregulated BCL6 expression. The increased expression of BCL6 further repressed the tumor suppressor PTEN and consequently enabled resistant cancer cell survival. Accordingly, targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. Our findings highlight the importance of BCL6 signaling in conquering solid tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.

NFIB promotes the progression of gastric cancer by upregulating circMAP7D1 to stabilize HER2 mRNA.

The present study evaluated the expression levels of nuclear factor I B (NFIB) in gastric cancer (GC) specimens and cells, and its regulatory roles were further elucidated. The expression levels of NFIB were examined in GC and paired normal specimens, and in human GC and normal gastric epithelial cells by reverse transcription­quantitative PCR. A circular RNA (circRNA) microarray was performed to identify the novel downstream circRNA of NFIB. Cell proliferation was determined by Cell Counting Kit­8 assay. Furthermore, cell cycle distribution and apoptosis were assessed using flow cytometry. Interactions between RNA were examined by RNA pulldown assay and the stability of target mRNA was evaluated using a mRNA stability assay. The results of the present study revealed that NFIB was upregulated in GC. Furthermore, silencing NFIB suppressed the proliferation of GC cells, whereas cell cycle arrest and apoptosis were enhanced. In addition, significant downregulation of circMAP7D1 (hsa_circ_0004093) was observed in GC cells infected with short hairpin RNA­NFIB. These findings indicated that circMAP7D1 may be a promising downstream molecule of NFIB in GC, and further functional analyses indicated that circMAP7D1 was involved in NFIB­modulated GC cell proliferation and apoptosis. Moreover, human epidermal growth factor receptor 2 (HER2) was identified as a novel target of circMAP7D1 in GC, and NFIB was able to increase the stability of HER2 mRNA through regulating circMAP7D1. In conclusion, the present findings indicated that NFIB expression was increased in GC. In addition, NFIB may promote the proliferation of GC cells and function through stabilizing HER2 mRNA by upregulating circMAP7D1. Notably, NFIB and its novel downstream signaling pathway may serve essential roles during the development of GC, and NFIB may be considered a promising candidate for the treatment of patients with GC.