Implication of KRT16, FAM129A and HKDC1 genes as ATF4 regulated components of the integrated stress response

Abstract

The ATF4 transcription factor is a key regulator of the adaptive integrated stress response (ISR) induced by various stresses and pathologies. Identification of novel transcription targets of ATF4 during ISR would contribute to the understanding of adaptive networks and help to identify novel therapeutic targets. We were previously searching for genes that display an inverse regulation mode by the transcription factors ATF4 and p53 in response to mitochondrial respiration chain complex III inhibition. Among the selected candidates the human genes for cytokeratine 16 (KRT16), anti-apoptotic protein Niban (FAM129A) and hexokinase HKDC1 have been found highly responsive to ATF4 overexpression. Here we explored potential roles of the induction of KRT16, FAM129A and HKDC1 genes in ISR. As verified by RT-qPCR, a dysfunction of mitochondrial respiration chain and ER stress resulted in a partially ATF4-dependent stimulation of KRT16, FAM129A and HKDC1 expression in the HCT116 colon carcinoma cell line. ISRIB, a specific inhibitor of ISR, was able to downregulate the ER stress-induced levels of KRT16, FAM129A and HKDC1 transcripts. An inhibition of ATF4 by RNAi attenuated the induction of KRT16, FAM129A and HKDC1 mRNAs in response to ER stress or to a dysfunctional mitochondrial respiration. The similar induction of the three genes was observed in another tumor-derived cervical carcinoma cell line HeLa. However, in HaCaT and HEK293T cells that display transformed phenotypes, but do not originate from patient-derived tumors, the ER stress-inducing treatments resulted in an upregulation of FAM129A and HKDC1, but not KRT16 transcripts, By a luciferase reporter approach we identified a highly active ATF4-responsive element within the upstream region of the KRT16 gene. The results suggest a conditional regulation of KRT16 gene by ATF4 that may be inhibited in normal cells, but engaged during cancer progression. Potential roles of KRT16, FAM129A and HKDC1 genes upregulation in adaptive stress responses and pathologies are discussed.

Utility of Extrapolating Human S1500+ Genes to the Whole Transcriptome: Tunicamycin Case Study

“…For example, pathways that were enriched in the whole transcriptome analysis are related to ATF4 and PERK, which are each known to be upregulated in the presence of tunicamycin. 21,26,34,42,48 The downregulation of the "HALLMARK_ANGIOGENESIS" pathway is consistent with the inhibition of angiogenesis by tunicamycin in mice. 49 In addition, regulation by tunicamycin of Cytochrome P450 metabolism and N-glycan/N-linked glycosylation expression is supported by previous research findings.…”

FAM129A regulates autophagy in thyroid carcinomas in an oncogene-dependent manner

“…Recently, FAM129A was identified as a novel target of ATF4, a key regulator of the adaptive integrated stress response (ISR). The authors showed that the level of FAM129A can confer a pro-survival function during ISR, through attenuation of the p53-dependent apoptotic responses (Evstafieva et al 2018).…”

The Effects of Lentivirus-Mediated Gene Silencing of RARβ on the Stemness Capability of Non-Small Cell Lung Cancer

“…Among these genes, TRIML2, FAM129A, EMP1, and SERPINE1 were involved in inducing tumorigenicity. FAM129A encodes for Niban, an anti-apoptotic protein that is overexpressed in many cancer [44]. This protein prevents apoptosis by releasing Mdm2 protein, which stimulates the proteasomal degradation of p53 protein [45].…”