Abstract
Chromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L) has been characterized to be a driver gene in hepatocellular carcinoma (HCC). However, the intrinsic connections between CHD1L and intestinal dysbacteriosis-related inflammation reaction in HCC progression remain incompletely understood. In this study, a specific correlation between CHD1L and nonmuscle isoform of myosin light chain kinase (nmMLCK/nmMYLK), a newly identified molecule associated NF-κB signaling transduction, was disclosed in HCC. CHD1L promotes nmMYLK expression and prevents lipopolysaccharide (LPS) induced tumor cell death. In vitro experiment demonstrated that overexpressed nmMYLK is essential for CHD1L to maintain HCC cell alive, while knocking down nmMYLK significantly attenuate the oncogenic roles of CHD1L. Mechanism analysis revealed that nmMYLK can prevent Caspase-8 from combining with MyD88, an important linker of TLRs signaling pathway, while, knocking down nmMYLK facilitate the MyD88 combines with Caspase-8 and lead to the proteolytic cascade of Caspase as well as the consequent cell apoptosis. Mechanism analysis showed that CHD1L promotes the nmMYLK expression potentially through upregulating the heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) expression, which can bind to myosin light chain kinase (MYLK) pre-mRNA and lead to the regnant translation of nmMYLK. In summary, this work characterizes a previously unknown role of CHD1L in preventing LPS-induced tumor cell death through activating hnRNP A2/B1-nmMYLK axis. Further inhibition of CHD1L and its downstream signaling could be a novel promising strategy in HCC treatment.
Highlights
Dysbacteriosis, characterized by excessive lipopolysaccharideinduced endotoxemia and activation of TLRs-NF-κB signaling, might occur after antibiotic therapy, surgery, chemotherapy, or radiotherapy of cancer
Chromodomain helicase/adenosine triphosphatase DNA-binding protein 1-like gene (CHD1L) promotes nmMYLK expression in hepatocellular carcinoma cells (HCC) To further study the mechanism of CHD1L, we have constructed the CHD1L overexpressed HCC cell line
Overexpressed nmMYLK in 7703 cells sion of CHD1L and myosin light chain kinase (MYLK) in different HCC cell lines including LO2, significantly reversed this phenotype when compared with the QGY-7703, HepG2, Huh7 was measured by quantitative real-time PCR (qRT-PCR) and western vector control cells, and this effect was enhanced after LPS
Summary
Dysbacteriosis, characterized by excessive lipopolysaccharideinduced endotoxemia and activation of TLRs-NF-κB signaling, might occur after antibiotic therapy, surgery, chemotherapy, or radiotherapy of cancer. Chromodomain helicase/adenosine triphosphatase DNA-binding protein 1-like gene (CHD1L) is originally verified in human hepatocellular carcinoma cells (HCC) and its oncogenic roles have been characterized in previous studies [1, 2]. Many studies revealed the oncogenic roles of CHD1L in different kinds of malignancies, such as ovarian carcinoma [3], bladder cancer [4], colorectal carcinoma [5], breast cancer [6], and lung adenocarcinoma [7], etc. Considering that dysbacteriosis is common in cancer patients, it is important to know how CHD1L works in the pathological microenvironment of dysregulated flora. MYLK gene encodes mainly two different catalytic protein isoforms. The short isoform named smooth muscle MYLK (smMYLK) is mainly expressed in smooth muscle tissue, while the long isoform generally exists in nonmuscle tissues (nmMYLK) [11].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
