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Immunotherapies targeting the PD-1/PD-L1 axis have become first-line treatments in multiple cancers. However, only a limited subset of individuals achieves durable benefits because of the elusive mechanisms regulating PD-1/PD-L1. Here, we report that in cells exposed to interferon-γ (IFNγ), KAT8 undergoes phase separation with induced IRF1 and forms biomolecular condensates to upregulate PD-L1. Multivalency from both the specific and promiscuous interactions between IRF1 and KAT8 is required for condensate formation. KAT8–IRF1 condensation promotes IRF1 K78 acetylation and binding to the CD247 (PD-L1) promoter and further enriches the transcription apparatus to promote transcription of PD-L1 mRNA. Based on the mechanism of KAT8–IRF1 condensate formation, we identified the 2142–R8 blocking peptide, which disrupts KAT8–IRF1 condensate formation and consequently inhibits PD-L1 expression and enhances antitumor immunity in vitro and in vivo. Our findings reveal a key role of KAT8–IRF1 condensates in PD-L1 regulation and provide a competitive peptide to enhance antitumor immune responses.

STING, an endoplasmic reticulum (ER) transmembrane protein, mediates innate immune activation upon cGAMP stimulation and is degraded through autophagy. Here, we report that activated STING could be transferred between cells to promote antitumor immunity, a process triggered by RAB22A-mediated non-canonical autophagy. Mechanistically, RAB22A engages PI4K2A to generate PI4P that recruits the Atg12–Atg5–Atg16L1 complex, inducing the formation of ER-derived RAB22A-mediated non-canonical autophagosome, in which STING activated by agonists or chemoradiotherapy is packaged. This RAB22A-induced autophagosome fuses with RAB22A-positive early endosome, generating a new organelle that we name Rafeesome (RAB22A-mediated non-canonical autophagosome fused with early endosome). Meanwhile, RAB22A inactivates RAB7 to suppress the fusion of Rafeesome with lysosome, thereby enabling the secretion of the inner vesicle of the autophagosome bearing activated STING as a new type of extracellular vesicle that we define as R-EV (RAB22A-induced extracellular vesicle). Activated STING-containing R-EVs induce IFNβ release from recipient cells to the tumor microenvironment, promoting antitumor immunity. Consistently, RAB22A enhances the antitumor effect of the STING agonist diABZI in mice, and a high RAB22A level predicts good survival in nasopharyngeal cancer patients treated with chemoradiotherapy. Our findings reveal that Rafeesome regulates the intercellular transfer of activated STING to trigger and spread antitumor immunity, and that the inner vesicle of non-canonical autophagosome originated from ER is secreted as R-EV, providing a new perspective for understanding the intercellular communication of organelle membrane proteins.

Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRASG12C mutant. Here we report that RAS-ON (RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-KrasG12D; Trp53R172H/+ mice. Mechanistically, RASON directly binds to KRASG12D/V and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRASG12D/V in the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers.

Transcription dysregulation is a salient characteristic of bladder cancer (BC), but no appropriate therapeutic target for it has been established. Here, we found that heterogeneous downregulation of histone H4 transcription factor (HINFP) was associated with senescence in BC tissues and that lower HINFP expression could predict an unfavorable outcome in BC patients. Knockout of HINFP transcriptionally inhibited H1F0 and H1FX to trigger DNA damage, consequently inducing cell senescence to repress the proliferation and growth of BC cells. However, the senescence-associated secretory phenotype, characterized by increases in MMP1/3, enhances the invasion and metastasis of non-senescent BC cells. Histone deacetylase inhibitors (HDACis) could efficiently eliminate the senescent cells induced by HINFP knockout to suppress the invasion and metastasis of BC cells. Our study suggests that HDACis, widely used in multiple cancer types in a clinical context, may also benefit BC patients with metastases induced by cell senescence.

Background Natural killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with a poor prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit potential novel therapeutic targets for the treatment of NKTL. Histone deacetylase (HDAC) inhibitor chidamide was recently approved for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) patients. However, its therapeutic efficacy in NKTL remains unclear. Methods We performed a phase II clinical trial to evaluate the efficacy of chidamide in 28 relapsed/refractory NKTL patients. Integrative transcriptomic, chromatin profiling analysis and functional studies were performed to identify potential predictive biomarkers and unravel the mechanisms of resistance to chidamide. Immunohistochemistry (IHC) was used to validate the predictive biomarkers in tumors from the clinical trial. Results We demonstrated that chidamide is effective in treating relapsed/refractory NKTL patients, achieving an overall response and complete response rate of 39 and 18%, respectively. In vitro studies showed that hyperactivity of JAK-STAT signaling in NKTL cell lines was associated with the resistance to chidamide. Mechanistically, our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect in vitro and in vivo. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of the JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. Conclusions Our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL. Trial registration: ClinicalTrials.gov, NCT02878278. Registered 25 August 2016, https://clinicaltrials.gov/ct2/show/NCT02878278

BRAF inhibitors (BRAFi) that target BRAF V600E kinase, a driver mutation found in 50% of melanomas, show a significant antitumor response, but the common emergence of acquired resistance remains a challenge. Abnormal expression of RAF isoforms CRAF and ARAF reactivates pERK1/2, which plays crucial roles in the acquisition of resistance of melanoma cells. However, the mechanisms of dysregulation of RAF isoforms in resistant melanoma cells remain unknown. Here, we identified NONO interacted with and stabilized both CRAF and ARAF in melanoma cells, and that NONO was acetylated at 198K by p300 acetyltransferase, which stabilized NONO via antagonizing its ubiquitination/degradation mediated by RNF8. The upregulation of both p300 and NONO promoted the rebound of pERK1/2 and the subsequent resistance of melanoma cells to BRAFi, and the activation of ERK1/2 in turn induced p300 to form a positive feedback loop in resistant melanoma cells. There was a positive correlation between p300 and NONO in resistant melanoma cells and clinical samples, and p300 inhibitor C646 overcame the resistance of resistant melanoma cells to BRAF inhibitors in vitro and in vivo. Our findings reveal that targeting the positive feedback loop of p300-NONO-CRAF/ARAF-pERK1/2 may be excellent strategies to overcome the resistance of BRAF inhibitors for melanoma patients.

The combination of immune checkpoint blockade (ICB) with chemotherapy significantly improves clinical benefit of cancer treatment. Since chemotherapy is often associated with adverse events, concomitant treatment with drugs managing side effects of chemotherapy is frequently used in the combination therapy. However, whether these ancillary drugs could impede immunotherapy remains unknown. Here, we showed that ∆9-tetrahydrocannabinol (THC), the key ingredient of drugs approved for the treatment of chemotherapy-caused nausea, reduced the therapeutic effect of PD-1 blockade. The endogenous cannabinoid anandamide (AEA) also impeded antitumor immunity, indicating an immunosuppressive role of the endogenous cannabinoid system (ECS). Consistently, high levels of AEA in the sera were associated with poor overall survival in cancer patients. We further found that cannabinoids impaired the function of tumor-specific T cells through CNR2. Using a knock-in mouse model expressing a FLAG-tagged Cnr2 gene, we discovered that CNR2 binds to JAK1 and inhibits the downstream STAT signaling in T cells. Taken together, our results unveiled a novel mechanism of the ECS-mediated suppression on T-cell immunity against cancer, and suggest that cannabis and cannabinoid drugs should be avoided during immunotherapy.

Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon-intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1-38 of Rab22a (Rab22a1-38) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a1-38 moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP-GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.

This article has been retracted. Please see the Retraction Notice for more detail: 10.1186/s13046-021-02204-1

Human single-stranded DNA-binding protein 1 (hSSB1) is required for the efficient recruitment of the MRN complex to DNA double-strand breaks and is essential for the maintenance of genome integrity. However, the mechanism by which hSSB1 recruits NBS1 remains elusive. Here, we determined that hSSB1 undergoes SUMOylation at both K79 and K94 under normal conditions and that this modification is dramatically enhanced in response to DNA damage. SUMOylation of hSSB1, which is specifically fine-tuned by PIAS2α, and SENP2, not only stabilizes the protein but also enhances the recruitment of NBS1 to DNA damage sites. Cells with defective hSSB1 SUMOylation are sensitive to ionizing radiation, and global inhibition of SUMOylation by either knocking out UBC9 or adding SUMOylation inhibitors significantly enhances the sensitivity of cancer cells to etoposide. Our findings reveal that SUMOylation, as a novel posttranslational modification of hSSB1, is critical for the functions of this protein, indicating that the use of SUMOylation inhibitors (e.g., 2-D08 and ML-792) may be a new strategy that would benefit cancer patients being treated with chemo- or radiotherapy.

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy., PD-L1 is highly expressed in triple-negative breast cancers (TNBC). Here, the authors show that nucleophosmin 1 (NPM1) transcriptionally activates PD-L1 expression and inhibits T cell activity in TNBC.

Gastric cancer (GC) is one of the most common malignancies worldwide. Due to the low rate of early detection, most GC patients were diagnosed as advance stages and had poor response to chemotherapy. Some studies found that Fumarate hydratase (FH) participated in the DNA damage response and its deficiency was associated with tumorigenesis in some cancers. In this study, we investigated the relationship between FH and cisplatin (CDDP) sensitivity in GC cell lines. We found that FH was the most significant gene which induced by CDDP treatment and the suppression of FH could enhance the cytotoxicity of CDDP. Miconazole Nitrate (MN) could inhibit FH activity and enhance the effect of CDDP in vitro and in vivo. We also investigated the significance of expression of FH in GC tissues. The FH expression, which was higher in GC tissues than in noncancerous tissues, was negatively associated with the prognosis of patients. Together, these results revealed that FH is a reliable indicator for response to CDDP treatment in GC and the inhibition of FH may be a potential strategy to improve the effects of CDDP-based chemotherapy.

Background MNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, high expresses in various cancers and is involved in cancer pathogenesis. However, mechanisms underlying its regulation in carcinogenesis are unclear. Methods The tissue microarray of colorectal cancer (CRC) was used to evaluate MNAT1 expressions in CRC tissues using immunohistochemistry, CRC cell lines were also detected MNAT1 expression using Western-blotting. MNAT1 and shMNAT1 vectors were constructed, and transfected into CRC cells. Cell growths of the transfected cells were observed using MTT and colony formation. The affects of MNAT1 on p53 expression were analyzed using Western-blotting and Real-time PCR. Immunoprecipitation assay was used to analyze the interaction p53 and MNAT1, and Western-blotting was used to test the effects of MNAT1 on p53 downstream molecules. The apoptosis of CRC cells with MNAT1 or shMNAT1 were analyzed using flow cytometry. BABL/c athymic nude mice were used to observe the effect of MNAT1 on CRC cell growth in vivo. Results MNAT1 was found to be overexpressed in CRC tissues and cells, and MNAT1 expressions in CRC tissue samples were associated with CRC carcinogenesis and poor patient outcomes. MNAT1-knockin increased CRC cell growth and colony formation, and MNAT1-knockdown dramatically decreased cell motility and invasion. MNAT1 physically interacted with p53, MNAT1 also increased the interaction of MDM2 with p53. Strikingly, MNAT1 mediated p53 ubiquitin-degradation. MNAT1 shortened p53 half-life, and ectopic MNAT1 expression decreased p53 protein stability. Moreover, MNAT1 induced RAD51 and reduced p21, cleaved-caspase3, cleaved-PARP and BAX expression. MNAT1 inhibited CRC cell apoptosis. shMANT1 decreased tumor growths in nude mice following p53 increase. Conclusion MNAT1 binds to p53, mediates p53 ubiquitin-degradation through MDM2, increases cell growth and decreases cell apoptosis, and finally promotes CRC malignance. MNAT1 binding to p53 and mediating p53 ubiquitin-degradation axis represents a novel molecular joint in the p53 pathway.

Background Distant metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear. Methods Quantitative RT-PCR (qRT-PCR), western blotting, cell growth, foci formation, migration and invasion assays, and xenograft mouse models were utilized to examine the expression levels and functions of the CXCL5/CXCR2 axis in NPC. A luciferase reporter assay, western blotting, immunofluorescence, and migration and invasion assays were used to identify and verify the ERK/GSK-3β/Snail signalling pathway. Results CXCL5 was significantly increased in the sera of NPC patients, and high expression levels of CXCL5/CXCR2 in NPC primary tissues indicated poor survival. CXCL5 and CXCR2 were upregulated in NPC cell lines. Ectopic expression of the CXCL5/CXCR2 axis promoted NPC cell migration and invasion in vitro and the formation of lung metastases in vivo. Mechanistically, the dual overexpression of CXCL5 and CXCR2 promoted cell spreading by inducing the epithelial-mesenchymal transition (EMT) through the activation of the ERK/GSK-3β/Snail signalling pathway. Conclusion The CXCL5/CXCR2 axis contributes to the EMT of NPC cells by activating ERK/GSK-3β/Snail signalling, and this axis may be a potential diagnostic marker and therapeutic target for patients with NPC. Electronic supplementary material The online version of this article (10.1186/s13046-018-0722-6) contains supplementary material, which is available to authorized users.

Background Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. Methods We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. Results The CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. Conclusions CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML. Electronic supplementary material The online version of this article (10.1186/s13045-017-0553-5) contains supplementary material, which is available to authorized users.

The existence of cancer stem cells, stem-like cancer cells (SLCCs), or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses: SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea (AET), a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C (MMC), a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.

Background Centrosomal protein 78 (CEP78) has been characterized as a component of the centrosome required for the regulation of centrosome-related events during the cell cycle, but its role in human cancers remains unclear. This study aimed to investigate the role and the clinical value of CEP78 in colorectal cancer (CRC). Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to examine CEP78 expression in CRC tissues and adjacent noncancerous tissues. The association between CEP78 expression and clinical outcomes of CRC patients was determined. The effect of CEP78 on cell growth was examined in vitro by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, colony formation, and flow cytometry assays and in vivo using a nude mouse model. Results The expression level of CEP78 was significantly lower in tumor tissues than in the adjacent normal tissues (P

MicroRNAs (miRNAs) may function as either oncogenes or tumor suppressors in the malignant progression of different tumor types. MiR-663 was recently reported to be decreased and identified as a tumor suppressor in gastric cancer. We also verified its role in repressing cell proliferation of a gastric cancer cell line. In this study, however, miR-663 was found to be upregulated in nasopharyngeal carcinoma (NPC) cells compared with human immortalized nasopharyngeal epithelium cells, using a miRNA microarray, and this higher expression was confirmed in NPC tissue samples. Indeed, inhibition of miR-663 impaired the proliferation of NPC cells in vitro and the NPC tumor growth of xenografts in nude mice. Mechanistically, miR-663 directly targeted p21(WAF1/CIP1) to promote the cellular G1/S transition, as the inhibitory effects of miR-663 on the G1/S transition could be rescued by p21(WAF1/CIP1) silencing. Our results imply that miR-663 may act as an oncogene in NPC. The newly identified miR-663/p21(WAF1/CIP1) axis clarifies the molecular mechanism of NPC cell proliferation and represents a novel strategy for the diagnosis and treatment of patients with NPC.

Downregulation of hSSB1, a single-stranded DNA-binding protein, causes increased radiosensitivity, defective checkpoint activation and genomic instability. However, the mechanisms of hSSB1 function in these responses remain to be uncovered. Here, we present evidence that hSSB1 directly binds p21 and this interaction may prevent p21 from ubiquitin-mediated degradation. Furthermore, both promotion of the G1/S transition and abrogation of the G2/M checkpoints induced by hSSB1 knockdown are partially dependent on p21. Most importantly, hSSB1 and p21 levels are positively correlated in human hepatocellular carcinomas (HCC), as determined by immunostaining. Therefore, hSSB1 may positively modulate p21 to regulate cell cycle progression and DNA damage response, implicating hSSB1 as a novel, promising therapeutic target for cancers such as HCC.

To identify genetic susceptibility loci for nasopharyngeal carcinoma (NPC), a genome-wide association study was performed using 464,328 autosomal SNPs in 1,583 NPC affected individuals (cases) and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genome-wide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The seven supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. We identified three new susceptibility loci, TNFRSF19 on 13q12 (rs9510787, Pcombined=1.53x10(-9), odds ratio (OR)=1.20), MDS1-EVI1 on 3q26 (rs6774494, Pcombined=1.34x10(-8), OR=0.84) and the CDKN2A-CDKN2B gene cluster on 9p21 (rs1412829, Pcombined=4.84x10(-7), OR=0.78). Furthermore, we confirmed the role of HLA by revealing independent associations at rs2860580 (Pcombined=4.88x10(-67), OR=0.58), rs2894207 (Pcombined=3.42x10(-33), OR=0.61) and rs28421666 (Pcombined=2.49x10(-18), OR=0.67). Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of pathways related to TNFRSF19 and MDS1-EVI1 in addition to HLA molecules.

Mutations of BRCA1-associated protein 1 (BAP1), a nuclear-localized deubiquitinating enzyme, had been documented in multiple human cancers. However, its role and clinical relevance in colorectal cancer is unknown. The purpose of this study was to reveal the prognostic significance of BAP1 in colorectal cancer. We performed quantitative PCR and Western blotting analyses to examine BAP1 expression in 8 cases of CRC tissues and matched adjacent non-cancerous tissues. And immunohistochemistry was used to evaluate BAP1 expression in archived 252 paraffin-embedded CRC specimens. We found that the mRNA and protein levels of BAP1 were down-regulated in 6 out of 8 cases of CRC tissues compared with their adjacent non-cancerous tissues. The BAP1 expression was closely correlated with age (p = 0.037), clinical stage (p = 0.001), T classification (p < 0.001), N classification (p < 0.001), and pathologic differentiation (p = 0.008) and histological type (p = 0.047) in CRC. The CRC patients with lower BAP1 expression survived shorter than those with higher BAP1 expression. Importantly, multivariate analysis demonstrated that BAP1 expression was an independent prognostic factor for CRC (p = 0.037). Collectively, we provide the first evidence that reduced BAP1 expression is associated with poor prognosis of CRC and BAP1 may serve as a novel prognostic biomarker for CRC.