Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis.

Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.

SIX4 activates Akt and promotes tumor angiogenesis.

Angiogenesis plays important roles in solid tumors progression. Growth factors such as vascular endothelial growth factors (VEGFs) can induce angiogenesis and hypoxia promotes the expression of VEGFs through activating hypoxia-inducible factor 1 (HIF-1α). However, the regulation of HIF-1α still not been fully understood. Here, we demonstrate that the Sine Oculis Homeobox Homolog 4 (SIX4) is up-regulated in colorectal cancer (CRC) and high expression of SIX4 predicts a poor prognosis. Overexpression of SIX4 enhances tumor growth and angiogenesis in vitro and in vivo, while knockdown of SIX4 inhibits tumor growth and angiogenesis. Furthermore, we show that SIX4 increases the expression of VEGF-A by coordinating with the HIF-1α. Mechanically, we explore that SIX4 up-regulates the expression of HIF-1α depending on Akt activation. Collectively, we demonstrate that SIX4 is functional in regulating tumor angiogenesis and SIX4 might be used as anti-angiogenic therapy in CRC.

Brg1 promotes liver fibrosis via activation of hepatic stellate cells.

Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Brg1, the core subunit of the SWI/SNF chromatin remodeling complex, has been proved to associated with nonalcoholic steatohepatitis which may progress to cirrhosis. Herein, we determined whether Brg1 regulates liver fibrosis and examined its mechanism by focusing on HSCs activation. In this study, we demonstrate that Brg1 is elevated in human and mouse fibrotic liver tissues and Brg1 mediate the profibrotic response in activated HSCs. Our data indicate that Brg1 regulates the activation of HSCs through TGFß/Smad signal pathway. Moreover, Brg1 deficiency mice displayed decreased HSCs activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. In addition, Brg1 expression is positively correlated with liver fibrosis in cirrhotic patients and may be a prognostic factor in HCC. Collectively, we demonstrate that Brg1 promotes liver fibrosis by activating HSCs and may represent a potential target for anti-fibrotic therapies.

Correction to: Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1ß/VEGFA signalling.

After the publication of this work [1] an error was noticed in Fig. 7e, in which the incorrect information is shown. The updated figure included in this correction now shows the quantification of tumor microvessel density. This correction does not affect the findings or conclusions of the article. Nevertheless, we apologize for the inconvenience.

Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1ß/VEGFA signalling.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common soft tissue sarcoma. The identification of the molecular mechanisms regulating GIST progression is vital for its treatment and prevention. Increasing reports have demonstrated that epigenetic alterations play critical roles in GIST development. However, the role of the histone demethylase KDM4D in GIST progression is poorly understood. METHODS: In clinically matched GIST tissues, KDM4D protein levels were measured by Western blot and immunohistochemical (IHC) staining. KDM4D mRNA levels were examined by quantitative real-time PCR (qRT-PCR). Bioinformatics analysis was used to examine KDM4D expression. The biological effects of KDM4D were investigated in vitro using CCK-8, BrdU/PI, wound healing, colony formation, tube formation and Transwell assays and in vivo using a xenograft mice model. Luciferase assays were used to assess regulation of HIF1ß gene promoter activity by KDM4D. ChIP assays were performed to assess KDM4D, H3K36me3 and H3K9me3 occupancy on the HIF1ß gene promoter. RESULTS: We observed a significant upregulation of KDM4D in GIST tissue compared with matched normal tissue and further explored the oncogenic function of KDM4D both in vitro and in vivo. Furthermore, we demonstrated that KDM4D directly interacted with the HIF1ß gene promoter and regulated its activity, promoting tumour angiogenesis and GIST progression both in vitro and in vivo. Finally, we demonstrated that KDM4D transcriptionally activates HIF1ß expression via H3K9me3 and H3K36me3 demethylation at the promoter region. CONCLUSIONS: Our findings reveal the important roles of the KDM4D/HIF1ß/VEGFA signalling pathway in GIST progression, and this pathway may act as a potential therapeutic target for GIST patients.

TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling.

BACKGROUND: Cellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resistance of various cancer cells. However, the role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear. METHODS: The expression of TRIB2 in colorectal cancer tissues and adjacent tissues was detected by immunohistochemistry and RT-PCR. The growth, cell cycle distribution and cellular senescence of colorectal cancer cells were evaluated by Cell Counting Kit-8 (CCK8) assay, flow cytometry detection and senescence-associated ß-galactosidase staining, respectively. Western blot, RT-PCR and luciferase assay were performed to determine how TRIB2 regulates p21. Immunoprecipitation (IP) and chromatin-immunoprecipitation (ChIP) were used to investigate the molecular mechanisms. RESULTS: We found that TRIB2 expression was elevated in CRC tissues compared to normal adjacent tissues and high TRIB2 expression indicated poor prognosis of CRC patients. Functionally, depletion of TRIB2 inhibited cancer cells proliferation, induced cell cycle arrest and promoted cellular senescence, whereas overexpression of TRIB2 accelerated cell growth, cell cycle progression and blocked cellular senescence. Further studies showed that TRIB2 physically interacted with AP4 and inhibited p21 expression through enhancing transcription activities of AP4. The rescue experiments indicated that silencing of AP4 abrogated the inhibition of cellular senescence induced by TRIB2 overexpression. CONCLUSION: These data demonstrate that TRIB2 suppresses cellular senescence through interaction with AP4 to down-regulate p21 expression. Therefore, TRIB2 could be a potential target for CRC treatment.

BRG1 promotes VEGF-A expression and angiogenesis in human colorectal cancer cells.

Angiogenesis plays an important role in tumor growth and progression in solid tumors. Vascular endothelial growth factor (VEGF) is one of the most critical and specific factors that stimulate both physiological and pathological angiogenesis. Here, we report a novel role of BRG1, the core subunit of SWI/SNF family complexes, in angiogenesis. In this study, we demonstrate that BRG1 is overexpressed in colorectal cancer and decreased expression of BRG1 not only blocks cell proliferation but remarkably inhibits the ability of HUVECs to form capillary-like structures. Moreover, our study shows that BRG1 can regulate the expression of VEGF-A by interacting with HIF-1α. Furthermore, we find VEGF-A is overexpressed in colorectal cancer and is positively correlated with BRG1 expression. Taken together, our study demonstrated that BRG1 can promote VEGF-A expression and angiogenesis in colorectal cancer and BRG1 may be a novel drug target for the treatment of colorectal cancer.

Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells.

Cardiomyocyte apoptosis is a major process in pathogenesis of a number of heart diseases, including ischemic heart diseases and cardiac failure. Ensuring survival of cardiac cells by blocking apoptotic events is an important strategy to improve cardiac function. Although the role of ER disruption in inducing apoptosis has been demonstrated, we do not yet fully understand how it influences the mitochondrial apoptotic machinery in cardiac cell models. Recent investigations have provided evidences that the prosurvival protein HCLS1-associated protein X-1 (Hax1) protein is intimately associated with the pathogenesis of heart disease, mitochondrial biology, and protection from apoptotic cell death. To study the role of Hax1 upon ER stress induction, Hax1 was overexpressed in cardiac cells subjected to ER stress, and cell death parameters as well as mitochondrial alterations were examined. Our results demonstrated that the Hax1 is significantly downregulated in cardiac cells upon ER stress induction. Moreover, overexpression of Hax1 protected from apoptotic events triggered by Tunicamycin-induced ER stress. Upon treatment with Tunicamycin, Hax1 protected from mitochondrial fission, downregulation of mitofusins 1 and 2 (MFN1 and MFN2), loss of mitochondrial membrane potential (∆Ψm), production of reactive oxygen species (ROS) and apoptotic cell death. Taken together, our results suggest that Hax1 inhibits ER stress-induced apoptosis at both the pre- and post-mitochondrial levels. These findings may offer an opportunity to develop new agents that inhibit cell death in the diseased heart.

TGF-ß regulates the proliferation of lung adenocarcinoma cells by inhibiting PIK3R3 expression.

PIK3R3, an isoform of class IA phosphoinositide 3-kinase (PI3K), specifically interacts with cell proliferation regulators, such as retinoblastoma and proliferation cell nuclear antigen, to promote cell proliferation. However, the mechanisms behind the upstream signaling pathway of PIK3R3 remain unclear to date. This study showed that PIK3R3 expression was regulated by transforming growth factor-ß (TGF-ß) signaling and that PIK3R3 mediated the TGF-ß-induced inhibition of lung adenocarcinoma cell proliferation. TGF-ß down-regulated PIK3R3 expression in lung adenocarcinoma cells. However, this TGF-ß-induced inhibition of cell proliferation can be attenuated by PIK3R3 overexpression. In addition, TGF-ß can attenuate the transcriptional activity of NKX2.1, a transcription factor that binds to the promoter of PIK3R3. This result indicated that TGF-ß regulated PIK3R3 expression by targeting NKX2.1. We confirmed the correlation between NKX2.1 and PIK3R3 in clinical samples. Therefore, the TGF-ß/NKX2.1/PIK3R3 axis is crucial in the TGF-ß-induced inhibition of cell proliferation, and the NKX2.1/PIK3R3 axis might become a target in TGF-ß receptor-repressed lung adenocarcinoma.

Machine learning model for prediction of permanent stoma after anterior resection of rectal cancer: A multicenter study.

BACKGROUND: The conversion from a temporary to a permanent stoma (PS) following rectal cancer surgery significantly impacts the quality of life of patients. However, there is currently a lack of practical preoperative tools to predict PS formation. The purpose of this study is to establish a preoperative predictive model for PS using machine learning algorithms to guide clinical practice. METHODS: In this retrospective study, we analyzed clinical data from a total of 655 patients who underwent anterior resection for rectal cancer, with 552 patients from one medical center and 103 from another. Through machine learning algorithms, five predictive models were developed, and each was thoroughly evaluated for predictive performance. The model with superior predictive accuracy underwent additional validation using both an independent testing cohort and the external validation cohort. The Shapley Additive exPlanations (SHAP) approach was employed to elucidate the predictive factors influencing the model, providing an in-depth visual analysis of its decision-making process. RESULTS: Eight variables were selected for the construction of the model. The support vector machine (SVM) model exhibited superior predictive performance in the training set, evidenced by an AUC of 0.854 (95 % CI:0.803-0.904). This performance was corroborated in both the testing set and external validation set, where the model demonstrated an AUC of 0.851 (95%CI:0.748-0.954) and 0.815 (95%CI:0.710-0.919), respectively, indicating its efficacy in identifying the PS. CONCLUSIONS: The model(https://yangsu2023.shinyapps.io/psrisk/) indicated robust predictive performance in identifying PS after anterior resection for rectal cancer, potentially guiding surgeons in the preoperative stratification of patients, thus informing individualized treatment plans and improving patient outcomes.

LDL-C and TC mediate the risk of PNPLA3 inhibition on cardiovascular diseases.

BACKGROUND: PNPLA3 is a promising target for the treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease. ARO-PNPLA3 is a drug that efficiently lowers PNPLA3 expression in hepatocytes at the mRNA level, resulting in a significant reduction in liver fat in Phase I clinical trials. However, the long-term effects and potential side effects of ARO-PNPLA3 are not well understood. METHODS: We conducted a two-sample, two-step Mendelian randomization (MR) analysis to investigate the association between PNPLA3 inhibition and 10 cardiovascular diseases (CVDs), as well as the role of lipid traits as mediators. We identified genetic variants near the PNPLA3 gene, which are linked to liver fat percentage, as instrumental variables for inhibiting PNPLA3. Additionally, positive control analyses on liver diseases were conducted to validate the selection of the genetic instruments. RESULTS: Genetically predicted PNPLA3 inhibition significantly increased the risk of coronary atherosclerosis (1.14, 95% CI 1.06, 1.23), coronary heart disease (1.14, 95% CI 1.08, 1.21), and myocardial infarction (1.16, 95% CI 1.08, 1.26). Suggestive associations were observed for increased risk of heart failure (1.09, 95% CI 1.02, 1.17, P = 0.0143) and atrial fibrillation (1.17, 95% CI 1.00, 1.36, P = 0.0468). Blood low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) mediated approximately 16-25%, 16-30%, and 14-22% of the associations between PNPLA3 inhibition and coronary atherosclerosis, myocardial infarction, and coronary heart disease, respectively. CONCLUSION: This study suggests that PNPLA3 inhibition increases the risk of major CVDs. Moreover, blood LDL-C and TC may mediate a significant proportion of the associations between PNPLA3 inhibition and coronary atherosclerosis, coronary heart disease, or myocardial infarction.

p55PIK-PI3K stimulates angiogenesis in colorectal cancer cell by activating NF-κB pathway.

Vascular growth factor (VEGF) is an important mediator of angiogenesis. PI3K plays essential roles in angiogenesis; however, the mechanisms and specific functions of individual isoforms of PI3K members in tumor angiogenesis regulation are still not fully understood. In this study, we evaluate the role of p55PIK, a PI3K regulatory subunit encoded by PIK3R3 gene, in tumor angiogenesis. We reported that overexpression of p55PIK in cancer cells up-regulated HIF-1α expression and increased VEGF expression. Furthermore, overexpression of p55PIK increased tumor angiogenesis in vivo and in vitro. Moreover, data indicated enhanced HIF-1α expression by p55PIK-PI3K depended on its ability to activate NF-кB signaling pathways, especially to increase the phosphorylation of p65 subunits of NF-κB. Our study suggested that p55PIK-PI3K was essential in regulating cancer cell-mediated angiogenesis and contributed to tumor growth and that the p55PIK provides a potential and specific target for new anti-angiogenesis drug development.

c-Myc enhances colon cancer cell-mediated angiogenesis through the regulation of HIF-1α.

Angiogenesis plays a pivotal role in tumor growth. The hypoxia-inducible factor 1, α subunit (HIF-1α)/vascular endothelial growth factor pathway is the most important pathway for regulating angiogenesis in the tumor microenvironment. c-Myc is an important oncogene that has many biological functions. In this study, we investigated the role of c-Myc in tumor angiogenesis. We found that the overexpression of c-Myc in colon cancer cells could promote the expression of HIF-1α and that of vascular endothelial growth factor. Moreover, we found that c-Myc regulated HIF-1α at the post-transcriptional level. The results revealed c-Myc-dependent regulation of HIF-1α instead of HIF-1α-dependent c-Myc regulation for the first time. They also showed that c-Myc was essential to regulate colon cancer cell-mediated angiogenesis and contributed to tumor growth. This research provides the theoretical basis for clinical trials of new therapeutic targets of c-Myc and HIF-1α in colon cancer cells.

Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report.

Synchronous gastrointestinal multiple primary tumors including gastric, colonic, and rectal cancers are rare. Moreover, it was a challenge to find an appropriate procedure without negatively impacting the overall outcome. We described the case of a 63-year-old woman who presented with a 4 month history of upper abdominal pain, acid regurgitation, and anemia. Gastroscopy with biopsy suggested early cancer of gastric antrum. Abdominal contrast-enhanced computerized tomography and colonoscopy revealed ascending colon and rectum tumors. She had no family history of malignancy. Endoscopic submucosal dissection was performed for gastric cancer, and the pathological result presented that it was poorly differentiated and invaded into deep submucosa. The laparoscopy-assisted radical surgery combined with distal gastrectomy, right hemicolectomy, and anterior resection of rectum was performed for these three tumors via eight ports and a 7 cm midline upper-abdominal incision. No other perioperative complications were encountered except postoperative ileus. The patient was discharged on the 12th postoperative day. The pathological results revealed gastric cancer (T1N0M0), right colonic cancer (T3N1M0), and rectal cancer (T2N0M0), indicating complete surgical resection. We reported that our laparoscopic approach for synchronous triple primary gastrointestinal malignant tumors was feasible and minimally invasive.

Inhibition of CARM1-Mediated Methylation of ACSL4 Promotes Ferroptosis in Colorectal Cancer.

Ferroptosis, which is caused by iron-dependent accumulation of lipid peroxides, is an emerging form of regulated cell death and is considered a potential target for cancer therapy. However, the regulatory mechanisms underlying ferroptosis remain unclear. This study defines a distinctive role of ferroptosis. Inhibition of CARM1 can increase the sensitivity of tumor cells to ferroptosis inducers in vitro and in vivo. Mechanistically, it is found that ACSL4 is methylated by CARM1 at arginine 339 (R339). Furthermore, ACSL4 R339 methylation promotes RNF25 binding to ACSL4, which contributes to the ubiquitylation of ACSL4. The blockade of CARM1 facilitates ferroptosis and effectively enhances ferroptosis-associated cancer immunotherapy. Overall, this study demonstrates that CARM1 is a critical contributor to ferroptosis resistance and highlights CARM1 as a candidate therapeutic target for improving the effects of ferroptosis-based antitumor therapy.

SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle.

MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post-transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post-translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip-mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri-methylation promotes tumor glycolysis and M2-like polarization of tumor-associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri-methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1-mediated tri-methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC.

PD-L1 methylation restricts PD-L1/PD-1 interactions to control cancer immune surveillance.

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) have enabled some patients with cancer to experience durable, complete treatment responses; however, reliable anti-PD-(L)1 treatment response biomarkers are lacking. Our research found that PD-L1 K162 was methylated by SETD7 and demethylated by LSD2. Furthermore, PD-L1 K162 methylation controlled the PD-1/PD-L1 interaction and obviously enhanced the suppression of T cell activity controlling cancer immune surveillance. We demonstrated that PD-L1 hypermethylation was the key mechanism for anti-PD-L1 therapy resistance, investigated that PD-L1 K162 methylation was a negative predictive marker for anti-PD-1 treatment in patients with non-small cell lung cancer, and showed that the PD-L1 K162 methylation:PD-L1 ratio was a more accurate biomarker for predicting anti-PD-(L)1 therapy sensitivity. These findings provide insights into the regulation of the PD-1/PD-L1 pathway, identify a modification of this critical immune checkpoint, and highlight a predictive biomarker of the response to PD-1/PD-L1 blockade therapy.

PRMT5 methylating SMAD4 activates TGF-ß signaling and promotes colorectal cancer metastasis.

Perturbations in transforming growth factor-ß (TGF-ß) signaling can lead to a plethora of diseases, including cancer. Mutations and posttranslational modifications (PTMs) of the partner of SMAD complexes contribute to the dysregulation of TGF-ß signaling. Here, we reported a PTM of SMAD4, R361 methylation, that was critical for SMAD complexes formation and TGF-ß signaling activation. Through mass spectrometric, co-immunoprecipitation (Co-IP) and immunofluorescent (IF) assays, we found that oncogene protein arginine methyltransferase 5 (PRMT5) interacted with SMAD4 under TGF-ß1 treatment. Mechanically, PRMT5 triggered SMAD4 methylation at R361 and induced SMAD complexes formation and nuclear import. Furthermore, we emphasized that PRMT5 interacting and methylating SMAD4 was required for TGF-ß1-induced epithelial-mesenchymal transition (EMT) and colorectal cancer (CRC) metastasis, and SMAD4 R361 mutation diminished PRMT5 and TGF-ß1-induced metastasis. In addition, highly expressed PRMT5 or high level of SMAD4 R361 methylation indicated worse outcomes in clinical specimens analysis. Collectively, our study highlights the critical interaction of PRMT5 and SMAD4 and the roles of SMAD4 R361 methylation for controlling TGF-ß signaling during metastasis. We provided a new insight for SMAD4 activation. And this study indicated that blocking PRMT5-SMAD4 signaling might be an effective targeting strategy in SMAD4 wild-type CRC.

Screening of binding proteins that interact with human Salvador 1 in a human fetal liver cDNA library by the yeast two-hybrid system.

Salvador promotes both cell cycle exit and apoptosis through the modulation of both cyclin E and Drosophila inhibitor of apoptosis protein in Drosophila. However, the cellular function of human Salvador (hSav1) is rarely reported. To screen for novel binding proteins that interact with hSav1, the cDNA of hSav1 was cloned into a bait protein plasmid, and positive clones were screened from a human fetal liver cDNA library by the yeast two-hybrid system. hSav1 mRNA was expressed in yeast and there was no self-activation and toxicity in the yeast strain AH109. Twenty proteins were found to interact with hSav1, including HS1 (haematopoietic cell specific protein1)-associated protein X-1 (HAX-1); neural precursor cell expressed, developmentally down-regulated 9, pyruvate kinase, liver and RBC, cytochrome c oxidase subunit Vb, enoyl coenzyme A hydratase short chain 1, and NADH dehydrogenase (ubiquinone) 1 beta subcomplex, demonstrating that the yeast two-hybrid system is an efficient method for investigating protein interactions. Among the identified proteins, there were many mitochondrial proteins, indicating that hSav1 may play a role in mitochondrial function. We also confirmed the interaction of HAX-1 and hSav1 in mammalian cells. This investigation provides functional clues for further exploration of potential apoptosis-related proteins in disease biotherapy.

Down-regulation of p110ß expression increases chemosensitivity of colon cancer cell lines to oxaliplatin.

This study examined the synergetic effect of class IA Phosphoinositide 3-kinases catalytic subunit p110ß knockdown in conjunction with oxaliplatin treatment on colon cancer cells. Down-regulation of p110ß by siRNA interference and oxaliplatin treatment were applied in colon cancer cell lines HT29, SW620 and HCT116. MTT assay was used to measure the inhibitory effect of p110ß knockdown on the proliferation of colon cancer cell lines. SubG1 assay and Annexin-V FITC/PI double-labeling cytometry were applied to detect cell apoptosis. And cell cycle was evaluated by using PI staining and flow cytometry. The expression of caspase 3, cleaved PARP, p-Akt, T-Akt and p110ß was determined by western blotting. The results suggested that down-regulation of p110ß expression by siRNA obviously reduced cell number via accumulation in G(0)-G(1) phase of the cell cycle in the absence of notablely increased apoptosis in colon cancer cell lines HT29 and SW620 (S phase arrest in HCT116). Moreover, inhibition of p110ß expression increased oxaliplatin-induced cell apoptosis and cell cycle arrest in HT29, HCT116 and SW620 cell lines. In addition, increases of cleaved caspase-3 and cleaved PARP induced by oxaliplatin treatment were determined by immunoblotting in p110ß knockdown group compared with normal control group and wild-type group. It is concluded that down-regulated expression of p110ß could inhibit colon cancer cells proliferation and result in increased chemosensitivity of colorectal cancer cells to oxaliplatin through augmentation of oxaliplatin-induced cell apoptosis and cell cycle arrest.