Incidence and hemodynamic feature of risky esophageal varices with lower hepatic venous pressure gradient.

Background: To examine the incidence of cirrhosis patients with high-risk esophageal varices (EV) who show hepatic venous pressure gradient (HVPG) < 10 mmHg and to identify their hemodynamic features. Methods: This prospective study consisted of 110 cirrhosis patients with EV, all with the candidate for primary or secondary prophylaxis. Sixty-one patients had red sign, and 49 patients were bleeders. All patients underwent both Doppler ultrasound and HVPG measurement. Results: There were 18 patients (16.4%) with HVPG < 10 mmHg. The presence of venous-venous communication (VVC) was more frequent in patients with HVPG < 10 mmHg (10/18) than in those with HVPG ≥ 10 mmHg (19/92; p = 0.0021). The flow volume in the left gastric vein (LGV) and the incidence of red sign were higher in the former (251.9 ± 150.6 mL/min; 16/18) than in the latter (181 ± 100.5 mL/min, p = 0.02; 45/92; p = 0.0018). The patients with red sign had lower HVPG (13.3 ± 4.5) but advanced LGV hemodynamics (velocity 13.2 ± 3.8 cm/s; flow volume 217.5 ± 126.6 mL/min), whereas those without red sign had higher HVPG (16.2 ± 4.6, p = 0.001) but poorer LGV hemodynamics (10.9 ± 2.3, p = 0.002; 160.1 ± 83.1, p = 0.02). Conclusion: Patients with high-risk EV with HVPG < 10 mmHg showed 16.4% incidence. Although low HVPG may be underestimated by the presence of VVC, the increased LGV hemodynamics compensates for the severity of portal hypertension, which may contribute to the development of red sign.

[A Case of Port Site Recurrence after Laparoscopic Distal Gastrectomy for Advanced Gastric Cancer].

It has been suggested that port site recurrence is a potential complication after laparoscopic distal gastrectomy for gastric cancer, especially considering the increased number of laparoscopic surgeries being performed. We encountered a case of an 84-year-old man who was diagnosed with 2 port site recurrences at the navel and right hypochondrium after laparoscopic distal gastrectomy(D2). Pathological diagnosis for the original tumor was tub2, pT4a, pN1(1/38), M0, pStage III A, and HER2(0). As first-line chemotherapy with S-1 plus CDDP for the port site recurrence failed, second-line chemotherapy with ramucirumab plus paclitaxel(RAM plus PTX)was administered. Although RAM plus PTX therapy induced shrinkage of the port site recurrence, liver metastasis was detected as a new lesion. RAM mono-therapy maintained good QOL for 18 months after surgery.

[Risk Evaluation and Prognostic Prediction of Colorectal Cancer in Elderly Patients Over 80 Years of Age].

This study aimed to investigate risk factors and prognosis ofcolorectal cancer in patients over 80 years ofage. Surgical risk was evaluated by colorectal POSSUM(CR-POSSUM)and prognosis by Glasgow prognostic score(GPS). The analysis included 56 patients aged over 80 years with colorectal cancer during 2002-2012. Mean operation time, blood loss, and period ofhospitalization were 130 min, 111 mL, and 19.9 days, respectively. Postoperative complications occurred in 26 patients (46.4%; complications group). The 5-year overall survival rate for patients with complication scores above 2 was 51.1%, compared to 82.3% in a control group, and patients in the complication group also exhibited a poorer prognosis. CR-POS SUM scores were significantly higher in the complication group than in the control group in PS, OS, and PMR. Further analysis revealed that patients with GPS 0 or 1 had a significantly higher 5-year survival rate(84.9%)than those with GPS2(38.9%, p <0.05).

[Curative Surgery for Advanced Gastric Cancer with Extensive Lymph Node Metastasis after Long-Term Chemotherapy].

A 65-year-old man was diagnosed with HER2-positive gastric cancer considered unresectable owing to multiple distant lymph node metastases. After long-term chemotherapy, the original lesion disappeared, while peri-gastric lymph node metastases remained. Therefore, we performed lower mediastinal lymph node dissection, total gastrectomy with regional lymph node dissection (D2) and cholecystectomy. Pathological evaluation indicated that the main gastric tumor showed complete response, while there was metastasis in the No.3 lymph nodes, which showed HER2 positivity (3+). At present, the patient has received Xeloda plus trastuzumab and remains relapse-free 5 months after conversion surgery.

Case-matched comparison of the short-term outcomes between laparoscopic and open abdominoperineal resection for rectal cancer.

PURPOSE: The aim of this study was to evaluate the short-term surgical outcomes of laparoscopic abdominoperineal resection (APR) for rectal cancer, by comparing it with a case-control series of open APR. METHODS: Fourteen patients with rectal cancer who underwent laparoscopic APR between August 2004 and November 2011 were compared with the open APR group of 14 patients matched for age, gender, and surgical procedure. RESULTS: There were no cases of conversion to laparotomy in the laparoscopic APR group and no mortality in either of the groups. The median operation was longer (P = 0.002), but the median amount of blood loss was smaller (P = 0.019), in the laparoscopic APR group. The median length of hospital stay of the laparoscopic APR group was 8 days, shorter than that of the open APR group (16 days, P < 0.001). The changes of the WBC count and serum CRP level after operations were significantly smaller in the laparoscopic APR group (P < 0.05). There were no significant differences between the groups in terms of the perioperative morbidity and readmission rates within 30 days. CONCLUSION: Patients undergoing laparoscopic APR had superior perioperative outcomes to those undergoing open APR, except for the longer operation.

[Two cases of rectal NET excised by laparoscopic surgery].

Even if grade 1 neuroendocrine tumors (NET) have low malignant potential, they may still be associated with lymph node metastasis. While the World Health Organization (WHO) classification requires determination of the grade of malignancy and presence of metastasis, it is also useful to evaluate tumor diameter, extent of invasion, and histological characteristics(cell variant, nuclear atypia, and ductal invasion). The authors present 2 cases of rectal NET excised by laparoscopic surgery. Considerations for surgical indications in rectal NET are made based on these case reports.

Minichromosome Maintenance Protein 7 is a potential therapeutic target in human cancer and a novel prognostic marker of non-small cell lung cancer.

BACKGROUND: The research emphasis in anti-cancer drug discovery has always been to search for a drug with the greatest antitumor potential but fewest side effects. This can only be achieved if the drug used is against a specific target located in the tumor cells. In this study, we evaluated Minichromosome Maintenance Protein 7 (MCM7) as a novel therapeutic target in cancer. RESULTS: Immunohistochemical analysis showed that MCM7 was positively stained in 196 of 331 non-small cell lung cancer (NSCLC), 21 of 29 bladder tumor and 25 of 70 liver tumor cases whereas no significant staining was observed in various normal tissues. We also found an elevated expression of MCM7 to be associated with poor prognosis for patients with NSCLC (P = 0.0055). qRT-PCR revealed a higher expression of MCM7 in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpressed MCM7 by cDNA microarray analysis. Suppression of MCM7 using specific siRNAs inhibited incorporation of BrdU in lung and bladder cancer cells overexpressing MCM7, and suppressed the growth of those cells more efficiently than that of normal cell strains expressing lower levels of MCM7. CONCLUSIONS: Since MCM7 expression was generally low in a number of normal tissues we examined, MCM7 has the characteristics of an ideal candidate for molecular targeted cancer therapy in various tumors and also as a good prognostic biomarker for NSCLC patients.

Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker.

The emphasis in anticancer drug discovery has always been on finding a drug with great antitumor potential but few side-effects. This can be achieved if the drug is specific for a molecular site found only in tumor cells. Here, we find the enhancer of zeste homolog 2 (EZH2) to be highly overexpressed in lung and other cancers, and show that EZH2 is integral to proliferation in cancer cells. Quantitative real-time PCR analysis revealed higher expression of EZH2 in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpress EZH2, using cDNA microarray analysis. Immunohistochemical analysis showed positive staining for EZH2 in 14 of 29 cases of bladder cancer, 135 of 292 cases of non-small-cell lung cancer (NSCLC), and 214 of 245 cases of colorectal cancer, whereas no significant staining was observed in various normal tissues. We found elevated expression of EZH2 to be associated with poor prognosis for patients with NSCLC (P = 0.0239). In lung and bladder cancer cells overexpressing EZH2, suppression of EZH2 using specific siRNAs inhibited incorporation of BrdU and resulted in significant suppression of cell growth, even though no significant effect was observed in the normal cell strain CCD-18Co, which has undetectable EZH2. Because EZH2 expression was scarcely detectable in all normal tissues we examined, EZH2 shows promise as a tumor-specific therapeutic target. Furthermore, as elevated levels of EZH2 are associated with poor prognosis of patients with NSCLC, its overexpression in resected specimens could prove a useful molecular marker, indicating the necessity for a more extensive follow-up in some lung cancer patients after surgical treatment.

Short-term outcomes of laparoscopic intersphincteric resection for lower rectal cancer and comparison with open approach.

BACKGROUND/AIMS: To evaluate the short-term surgical outcomes of laparoscopic intersphincteric resection (ISR) for lower rectal cancer, and to compare them with a case-control series of open ISR. METHODS: Between July 2002 and March 2011, 29 patients with lower rectal cancer underwent laparoscopic ISR, and 22 of 29 patients who underwent laparoscopic ISR were compared with the control open ISR group of patients matched for age, gender, operative procedure and pathological stage. RESULTS: There was no perioperative mortality, 8 complications occurred in 7 patients, and the morbidity rate was 24.1% (7/29). Leakage occurred in 1 patient (3.4%) in the laparoscopic ISR group. Regarding the matched case-control study, the operative time was significantly longer (p = 0.0007), but blood loss was significantly lower (p = 0.0003) in the laparoscopic ISR group. The median postoperative hospital stay was 8 days in the laparoscopic ISR group, which was significantly shorter than in the open ISR group (14 days). Postoperative complication rates were similar. In the laparoscopic ISR group, the levels of C-reactive protein on postoperative days 1-3 were significantly lower than in the open ISR group. CONCLUSIONS: Laparoscopic ISR for lower rectal cancer provides benefits in the early postoperative period without increasing morbidity or mortality.

[Treatment of lateral node metastasis from lower rectal cancer].

Lateral lymphatics of the rectum originate in the area where branches of the inferior hypogastric plexus and the middle rectal vessels from the internal iliac vessels enter the mesorectum below the level of the peritoneal reflection in the pelvis, then reach the bifurcation of iliac vessels along the internal iliac vessels. Among lateral lymph nodes, the middle rectal, obturator, and internal iliac lymph nodes are important from the viewpoint of both the incidence of metastais and treatment effects. Although total mesorectal excision (TME) had become the standard surgical treatment for rectal cancer by the 1990s, this technique does not treat lateral node metastasis. A randomized clinical trial of TME versus D3 lymphadenectomy (JCOG0212) was started in 2003, and the registration of 701 patients with lower rectal cancer was completed in August 2010. The results of this clinical trial are highly anticipated. In Japan, where the rate of local recurrence after surgery is low, patients at high risk of local recurrence such as those with lateral node metastasis, T4 disease, and multiple lymph node metastases in the mesorectum should be selected to receive preoperative chemoradiation. Japanese surgeons who treat rectal cancers are in an advantageous position because they have the additional measure of lateral node dissection along with TME and chemoradiotherapy.

A novel multimodal approach for locally advanced rectal cancer involving the pelvic sidewall.

BACKGROUND/AIMS: Total mesorectal excision (TME) is the standard surgery for locally advanced rectal cancer. In instances when the primary tumor invades adjacent organs, en-bloc excision is required for a curative resection. However, when lateral pelvic lymph node metastases involve the pelvic sidewall, treatment strategy is not established yet. METHODS: We here report on a case treated with a novel multimodal approach consisting of neoadjuvant chemoradiotherapy, followed by TME plus extended lateral pelvic lymph node dissection and en-bloc resection of the internal iliac artery and vein. RESULTS: There were no complications. Serial sections of the rectum showed only fibrosis and inflammatory cell aggregation. None of the mesorectal nodes contained tumor cells, but one each of the right and left lateral pelvic nodes demonstrated residual adenocarcinoma with foci of necrosis and fibrosis. Chemoradiotherapy increased the circumferential resection margin from 0 mm to 2 mm. An additional 5 mm clearance was obtained following resection of the internal iliac vessels yielding a total clearance margin of 7 mm. The patient remained free of disease 2.5 years after surgery. CONCLUSION: This seems to be the only strategy offering the possibility of cure for such a condition.

Accuracy of high-resolution magnetic resonance imaging in preoperative staging of rectal cancer.

BACKGROUND: To achieve better prognosis and quality of life for patients with rectal cancer, extent of surgery and neoadjuvant chemoradiotherapy should accurately reflect disease extent. The aim of this study was to evaluate accuracy of high-resolution magnetic resonance imaging (HRMRI) for preoperative staging of rectal cancer. METHODS: Between 2001 and 2003, 104 patients with primary rectal cancer were examined with HRMRI and underwent radical surgery. Transmural invasion depth and lymph node metastasis were assessed prospectively and classified according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system by both HRMRI and histopathology, and results were compared. Criteria for mesorectal and lateral pelvic lymph node involvement were short-axis diameters of > or =5 mm and > or =4 mm, respectively. RESULTS: There were 15 pT1, 25 pT2, 50 pT3, and 14 pT4 tumors. Overall accuracy rate for transmural invasion depth was 84%. The mesorectal fascia could be visualized in 98% of patients. Twenty-three patients had mesorectal fascia involvement and the overall accuracy rate was 96% (sensitivity, 96%; specificity, 96%). Fifty-three patients had mesorectal lymph node metastasis and the overall accuracy rate was 74% (sensitivity, 83%; specificity, 64%). Lateral pelvic lymph node metastasis was observed in 15 patients and the overall accuracy rate was 87% (sensitivity, 87%; specificity, 87%). CONCLUSIONS: HRMRI was moderately accurate for prediction of mesorectal lymph node metastasis and highly accurate regarding transmural invasion depth, and mesorectal fascia and lateral pelvic node involvement. Therefore, HRMRI appears useful for preoperative decision-making in rectal cancer treatment.

Efficacy and Safety of Deep Sedation in Percutaneous Radiofrequency Ablation for Hepatocellular Carcinoma.

INTRODUCTION: Radiofrequency ablation (RFA) has been accepted as safe and effective for treating early-stage hepatocellular carcinoma (HCC). However, it often causes severe pain. Therefore, in this study, we performed RFA under deep sedation and investigated its efficacy and safety. METHODS: We conducted a retrospective study including 511 HCC patients who received approximately 886 RFA treatments between December 2014 and November 2016 at our institution. Respiratory depression was defined as oxygen saturation of below 90%; and severe body movement was defined as movement caused by pain, which was managed by lowering the power of the generator. Factors associated with respiratory depression and severe body movement were examined via univariate and multivariate regression analyses. RESULTS: Respiratory depression occurred in 15.3% of the patients and severe body movement in 26.5% of the patients. In the multivariate analysis, BMI (≥ 25 kg/m2, odds ratio [OR] = 1.75, P = 0.035) and longer ablation (≥ 10 min, OR = 2.59, P = 0.002) were significant respiratory depression-related factors. Male sex (OR = 2.02, P = 0.005), Child-Pugh class A (odds ratio = 1.96, P = 0.018), and longer ablation (≥ 10 min, OR = 3.03, P < 0.001) were significant factors related to severe body movement. CONCLUSION: Deep sedation for RFA can be performed safely and effectively. Higher BMI and longer ablation were risk factors for respiratory depression and male sex, Child-Pugh class A, and longer ablation were independent predictors of severe body movement during RFA under deep sedation.

Intersphincteric resection for very low rectal adenocarcinoma: univariate and multivariate analyses of risk factors for recurrence.

BACKGROUND: The aim of this study was to analyze the risk factors for local and distant recurrence after intersphincteric resection (ISR) for very low rectal adenocarcinoma. METHODS: One hundred twenty consecutive patients with T1-T3 rectal cancers located 1-5 (median 3) cm from the anal verge underwent ISR. Univariate and multivariate analyses of prospectively recorded clinicopathologic parameters were performed. RESULTS: Fifty patients had disease categorized as stage I, 21 as stage II, 46 as stage III, and 3 as stage IV on the basis of International Union Against Cancer tumor, node, metastasis staging system. Median follow-up time was 3.5 years. The 3-year rates of local and distant recurrence were 6% and 13%, respectively. Univariate analysis of the risk factors for local recurrence revealed pathologic T, pathologic stage, focal dedifferentiation, microscopic resection margins, and preoperative serum CA 19-9 level to be statistically significant. Multivariate analysis showed resection margin, focal dedifferentiation, and serum CA 19-9 level to be independently significant. Univariate analysis of the risk factors for distant recurrence indicated tumor location, combined resection, tumor annularity, pathologic N, lateral pelvic lymph node metastasis, pathologic stage, histologic grade, lymphovascular invasion, perineural invasion, and adjuvant chemotherapy to be significant. Multivariate analysis identified pathologic N, histologic grade, and tumor location to be independently significant. CONCLUSION: Profiles of risk factors for local and distant recurrences after ISR are different. With local recurrence, the resection margin, focal dedifferentiation, and serum CA 19-9 level are important. For distant recurrence, the lymph node status, histologic grade, and tumor location need to be taken into account.

Percutaneous Ablation for Hepatocellular Carcinoma: Comparison of Various Ablation Techniques and Surgery.

Image-guided percutaneous ablation is considered best in the treatment of early-stage hepatocellular carcinoma (HCC). Ablation is potentially curative, minimally invasive, and easily repeatable for recurrence. Ethanol injection used to be the standard in ablation. However, radiofrequency ablation has recently been the most prevailing ablation method for HCC. Many investigators have reported that radiofrequency ablation is superior to ethanol injection, from the viewpoints of treatment response, local tumor curativity, and overall survival. New-generation microwave ablation can create a larger ablation volume in a shorter time period. Further comparison studies are, however, mandatory between radiofrequency ablation and microwave ablation, especially in terms of complications and long-term survival. Irreversible electroporation, which is a non-thermal ablation method that delivers short electric pulses to induce cell death due to apoptosis, requires further studies, especially in terms of long-term outcomes. It is considerably difficult to compare outcomes in ablation with those in surgical resection. However, radiofrequency ablation seems to be a satisfactory alternative to resection for HCC 3 cm or smaller in Child-Pugh class A or B cirrhosis. Furthermore, radiofrequency ablation may be a first-line treatment in HCC 2 cm or smaller in Child-Pugh class A or B cirrhosis. Various innovations would further improve outcomes in ablation. Training programs may be effective in providing an excellent opportunity to understand basic concepts and learn cardinal skills for successful ablation. Sophisticated ablation would be more than an adequate alternative of surgery for small- and possibly middle-sized HCC.

Comparison of integrated whole-body PET/MR and PET/CT: Is PET/MR alternative to PET/CT in routine clinical oncology?

PURPOSE: To compare the diagnostic accuracy of whole-body PET/CT and integrated PET/MR in relation to the total scan time durations. METHODS: One hundred and twenty-three (123) patients (40 males and 83 females; mean age 59.6 years; range 20-83 years) with confirmed primary cancer and clinical suspicion of metastatic disease underwent whole-body 18F-FDG-PET/CT and 18F-FDG-PET/MR. Data acquisition was done after intravenous administration of 110-301 MBq radioactivity of 18F-FDG, and PET/MR data were acquired after the PET/CT data acquisition. The mean uptake times for PET/CT and PET/MR acquisition were 68.0 ± 8.0 and 98.0 ± 14 min, respectively. Total scan time was 20.0 and 25.0 min for whole-body PET/CT and PET/MR imaging. RESULTS: The reconstructed PET/CT and PET/MR data detected 333/355 (93.8 %) common lesions in 111/123 (90.2 %) patients. PET/CT and PET/MR alone detected 348/355 and 340/355 lesions, respectively. No significant (p = 0.08) difference was observed for the overall detection efficiency between the two techniques. On the other hand, a significant difference was observed between the two techniques for the detection of lung (p = 0.003) and cerebrospinal (p = 0.007) lesions. The 15 lesions identified by PET/CT only included 8 lung, 3 lymph nodes, 2 bone, and 1 each of peritoneal and adrenal gland lesions. On the other hand, 7 (6 brain metastatic lesions and 1 bone lesion) were identified by PET/MR only. CONCLUSION: Integrated PET/MR is a feasible whole-body imaging modality and may score better than PET/CT for the detection of brain metastases. To further prove diagnostic utility, this technique requires further clinical validation.

Laparoscopic resection of synchronous colorectal cancers in separate specimens.

INTRODUCTION: Laparoscopic approaches are increasingly being used in patients with colorectal cancer, but the feasibility of laparoscopic resection of synchronous colorectal cancers in separate specimens remains unknown. In such cases, it is necessary to consider the site of port placement, sequence of dissection, choice of specimen extraction sites, specimen handling, and extracorporeal anastomosis sites. Moreover, the need for complete mesenteric dissection in two areas, removal of two separate specimens containing malignancies, and two anastomoses elicit unique questions related to technical considerations. The aim of this study was to determine the feasibility of laparoscopic resection of two separate specimens containing malignancies for multiple synchronous colorectal cancers. METHODS: Between June 2001 and January 2013, 1341 patients with colorectal cancer underwent laparoscopic surgery at our institution. Of them, 11 patients underwent laparoscopy-assisted combined resection of two separate colorectal specimens for multiple synchronous primary colorectal cancers. We retrospectively reviewed their surgical outcomes. RESULTS: All procedures were completed laparoscopically without perioperative mortality. Patients underwent right-sided colon resection for right-sided cancer and left-sided or rectal resection for left-sided colon or rectal cancer. The median duration of surgery was 296 min, and the median blood loss was 65 mL. Median time to first postoperative liquid and solid intake was 1 day and 3 days, respectively. Most patients were discharged on postoperative day 8. With regard to postoperative complications, two patients had a surgical-site infection. CONCLUSION: Laparoscopic resection of two separate colorectal specimens for multiple synchronous primary colorectal cancers is a feasible and safe procedure.

Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G(1)/S transition.

Although a number of JmjC-containing histone demethylases have been identified and biochemically characterized, pathological roles of their dysfunction in human disease such as cancer have not been well elucidated. Here, we report the Jumonji domain containing 2A (JMJD2A) is integral to proliferation of cancer cells. Quantitative real-time PCR analysis revealed higher expression of JMJD2A in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P<0.0001). Immunohistochemical analysis also showed positive staining for JMJD2A in 288 out of 403 lung cancer cases, whereas no staining was observed in lung normal tissues. Suppression of JMJD2A expression in lung and bladder cancer cells overexpressing this gene, using specific siRNAs, inhibited incorporation of BrdU and resulted in significant suppression of cell growth. Furthermore, JMJD2A appears to directly transactivate the expression of some tumor associated proteins including ADAM12 through the regulation of histone H3K9 methylation. As expression levels of JMJD2A are low in normal tissues, it may be feasible to develop specific inhibitors targeting the enzyme as anti-tumor agents which should have a minimal risk of adverse reaction.

The oncogenic polycomb histone methyltransferase EZH2 methylates lysine 120 on histone H2B and competes ubiquitination.

The histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation-Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.

Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression.

Although the physiologic significance of lysine methylation of histones is well known, whether lysine methylation plays a role in the regulation of nonhistone proteins has not yet been examined. The histone lysine methyltransferase SETD8 is overexpressed in various types of cancer and seems to play a crucial role in S-phase progression. Here, we show that SETD8 regulates the function of proliferating cell nuclear antigen (PCNA) protein through lysine methylation. We found that SETD8 methylated PCNA on lysine 248, and either depletion of SETD8 or substitution of lysine 248 destabilized PCNA expression. Mechanistically, lysine methylation significantly enhanced the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retarded the maturation of Okazaki fragments, slowed DNA replication, and induced DNA damage, and cells expressing a methylation-inactive PCNA mutant were more susceptible to DNA damage. An increase of methylated PCNA was found in cancer cells, and the expression levels of SETD8 and PCNA were correlated in cancer tissue samples. Together, our findings reveal a function for lysine methylation on a nonhistone protein and suggest that aberrant lysine methylation of PCNA may play a role in human carcinogenesis.