X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability1. Causal mutations have been found in approximately 90 X-linked genes2; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD Finger 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of ~7,000 refseq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in up-regulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish developing brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signaling and developmental pathways3. Our findings suggest that an imbalance of histone methylation dynamics plays a critical role in XLMR.

Background: The transforming growth factor-β (TGF-β) signaling pathway has been shown to play an important role in various cellular processes including growth inhibition, cell migration, tumor invasion, epithelial-mesenchymal transition, and immune-suppression. TGF-βs are often overexpressed in various types of cancers, and the anti-TGF-β therapy has been pursued intensively for cancer treatment. Results: GFH018 is a potent, selective inhibitor of TGF-βRI with a kinase inhibition activity IC50 of 70.5 nM. Our studies demonstrated that GFH018 could inhibit TGF-β-induced SMAD phosphorylation and migration of tumor cells. GFH018 is a potent immune regulator in that it could inhibit in vitro Treg cell induction and reverse M2 phenotype to M1, leading to increased pro-inflammatory cytokine production. In addition, GFH018 exhibited a significant inhibitory effect on in vitro angiogenesis formation assay. Importantly, GFH018 has shown promising anti-tumor efficacy in multiple in vivo mouse syngeneic models as a monotherapy as well as in combination with an anti-PD-(L)1 antibody. Following oral administration, GFH018 demonstrated fast absorption, and high oral bioavailability in preclinical animal species including mouse, rat, and dog. Results from the toxicology studies in rat and dog have also supported further development of GFH018. Conclusion: GFH018 has the potential to be developed as a monotherapy or combinational therapy with checkpoint inhibitors for advanced solid tumor patients. The first-in-human clinical trial is scheduled in 2019. Citation Format: Gang Hu, Rong Zhao, Fusheng Zhou, Jiong Lan, Biao Zheng, Qiang LU, Jianyu Lu, Lifang Wu, Fei Sun, Lihong Hu, Shuhua Han, Haijun Tong, Yuanfeng Xia, Wei Li, Liping Ma, Ying Chen, Charles Ding, Chichung Chan, Shuhui Chen. GFH018, a novel TGF-βRI inhibitor, for the treatment of advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3072.

Malignant melanoma is a highly aggressive neoplasia of melanocytic origin. In part because of the lack of effective treatment methods, the incidence and mortality rates of this disease continue to increase. Rapidly accumulating evidence suggests that dysregulation of epigenetic mechanisms, including DNA methylation/demethylation, chromatin modification, and remodeling, and diverse activities of noncoding RNAs, play a central role in the pathogenesis of melanoma. The epigenetic mark 5-hydroxymethylcytosine (5-hmC) has attracted interest since 2009, when it was shown that ten-eleven translocation proteins can enzymatically convert 5-methylcytosine into 5-hmC, a key intermediate of DNA demethylation. Factors that regulate DNA hydroxymethylation are frequently altered in cancer, leading to deregulation of 5-hmC levels. In this review, we will discuss the relationship between melanoma and DNA hydroxymethylation, the regulation of DNA hydroxymethylation, and defects in this pathway in melanoma.

BACKGROUND Intersphincteric resection (ISR), the ultimate anus-preserving technique for ultralow rectal cancers, is an alternative to abdominoperineal resection (APR). The failure patterns and risk factors for local recurrence and distant metastasis remain controversial and require further investigation. AIM To investigate the long-term outcomes and failure patterns after laparoscopic ISR in ultralow rectal cancers. METHODS Patients who underwent laparoscopic ISR (LsISR) at Peking University First Hospital between January 2012 and December 2020 were retrospectively reviewed. Correlation analysis was performed using the Chi-square or Pearson's correlation test. Prognostic factors for overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were analyzed using Cox regression. RESULTS We enrolled 368 patients with a median follow-up of 42 mo. Local recurrence and distant metastasis occurred in 13 (3.5%) and 42 (11.4%) cases, respectively. The 3-year OS, LRFS, and DMFS rates were 91.3%, 97.1%, and 90.1%, respectively. Multivariate analyses revealed that LRFS was associated with positive lymph node status [hazard ratio (HR) = 5.411, 95% confidence interval (CI) = 1.413-20.722, P = 0.014] and poor differentiation (HR = 3.739, 95%CI: 1.171-11.937, P = 0.026), whereas the independent prognostic factors for DMFS were positive lymph node status (HR = 2.445, 95%CI: 1.272-4.698, P = 0.007) and (y)pT3 stage (HR = 2.741, 95%CI: 1.225-6.137, P = 0.014). CONCLUSION This study confirmed the oncological safety of LsISR for ultralow rectal cancer. Poor differentiation, (y)pT3 stage, and lymph node metastasis are independent risk factors for treatment failure after LsISR, and thus patients with these factors should be carefully managed with optimal neoadjuvant therapy, and for patients with a high risk of local recurrence (N + or poor differentiation), extended radical resection (such as APR instead of ISR) may be more effective.