NDFIP1 limits cellular TAZ accumulation via exosomal sorting to inhibit NSCLC proliferation

NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors,but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown.Besides,the WW domain containing proteins can be recognized by NDFIP1,resulted in the loading of the target proteins into exosomes.However,whether WW domain-containing transcription regulator 1(WWTR1,also known as TAZ)can be packaged into exosomes by NDFIP1 and if so,whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent.Here,we first found that NDFIP1 was low expressed in NSCLC samples and cell lines,which is associated with shorter OS.Then,we confirmed the interaction between TAZ and NDFIP1,and the existence of TAZ in exosomes,which requires NDFIP1.Critically,knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate.And the cellular TAZ level could be altered by exosome secretion.Furthermore,NDFIP1 inhibited proliferation in vitro and in vivo,and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout.Moreover,TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples,and the serum exosomal TAZ level was lower in NSCLC patients.In summary,our data uncover a new tumor suppressor,NDFIP1 in NSCLC,and a new exosome-related regulatory mechanism of TAZ.

Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics

SI RT6 is an important histone modifying protein that regulates DNA repair,telomere maintenance,energy me-tabolism,and target gene expression.Recently SIRT6 has been identifi ed as a tumor suppressor and is down-regulated in certain cancer types,but not in other can-cers.From deposited gene profi ling studies we found that SIRT6 was overexpressed in prostate tumors,compared with normal or paratumor prostate tissues.Tissue micro-array studies confi rmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts.Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cy-cle,increased apoptosis,elevated DNA damage level and decrease in BCL2 gene expression.Moreover,SIRT6-de-fi ciency reduced cell viability and enhanced chemothera-peutics sensitivity.Taken together,this study provides the fi rst evidence of SIRT6 overexpression in human prostate cancer,and SIRT6 regulation could be exploited for pros-tate cancer therapy.

Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage

SIRT6 is a NAD＊-dependent histone deacetylase and has been implicated in the regulation of genomic stability, DNA repair, metabolic homeostasis and several diseases. The effect of SIRT6 in cerebral ischemia and oxygen/glucose deprivation （OGD） has been reported, however the role of SIRT6 in oxidative stress damage remains unclear. Here we used SH-SY5Y neuronal cells and found that overexpression of SIRT6 led to decreased cell viability and increased necrotic cell death and reactive oxygen species （ROS） production under oxidative stress. Mechanistic study revealed that SlRT6 induced autophagy via attenuation of AKT signaling and treatment with autophagy inhibitor 3-MA or knockdown of autophagy-related protein Atg5 rescued HzO2-induced neuronal injury. Conversely, SIRT6 inhibition suppressed autophagy and reduced oxidative stressinduced neuronal damage. These results suggest that SIRT6 might be a potential therapeutic target for neuroprotection.

Effect of ischaemic brain injury on sexual function in adult mice

Objective:Priapism refers to a condition with persistent abnormal erection of the penis,which is usually caused by disease or injury in the brain or spinal cord,or obstruction to the outflow of blood through the dorsal vein at the root of the penis,without sexual desires.The effect of cerebral ischaemia on sexual function is unknown.The aim of this study is to explore whether priapism occurs in adult mice.Furthermore,we examined the relationship between priapism and the region of infarct in the brain.Design:Adult male CD-1 mice who underwent permanent middle cerebral artery occlusion(pMCAO)were closely examined from 2 hours to 14 days postoperation.Results:We found that priapism occurs in∼80%of the mice with pMCAO,which could persist up to 14 days.Further study has demonstrated that the occurrence of priapism is related to the infarct region:priapism is found only in mice with ischaemic injury extending to the hypothalamus and the hippocampus regions.Conclusion:Our result suggested priapism may be used as a deep brain injury marker for evaluating brain injury in mice after pMCAO.