LINC00839 promotes colorectal cancer progression by recruiting RUVBL1/Tip60 complexes to activate NRF1

Abstract

The long noncoding RNA LINC00839 has been shown to be involved in the progression of some cancer types, such as bladder cancer, prostate cancer, breast cancer, and neuroblastoma. However, if LINC00839 has roles in colorectal cancer (CRC), it has not been elucidated so far. Here, we focus on the biological role and involved mechanisms of LINC00839 in CRC. We show that LINC00839 is selectively upregulated in CRC and locates to the nucleus. High expression of LINC00839 is associated with poor outcomes in CRC patients. Functional experiments show that LINC00839 promotes CRC proliferation, invasion, and metastasis in vitro and in vivo. Mechanistically, LINC00839 recruits Ruvb1 to the Tip60 complex and increases its acetylase activity. LINC00839 guides the complex to the NRF1 promoter and promotes acetylation of lysines 5 and 8 of histones H4, thereby upregulating the expression of NRF1. Subsequently, NRF1 activates mitochondrial metabolism and biogenesis, thereby promoting CRC progression. In summary, our study reports on a mechanism by which LINC00839 positively regulates NRF1, thus promoting mitochondrial metabolism and biogenesis, as well as CRC progression.

The chromatin-associated RNAs in gene regulation and cancer

“…Moreover, caRNAs can participate in transcriptional regulation and cancer progression by interacting with epigenetic factors. The latest research found that lncRNA LINC00839 acts as an RNA scaffold to recruit transcriptional activator RuvB-like AAA ATPase 1/Lysine Acetyltransferase 5 (Ruvb1/KAT5) complexes to the Nuclear Respiratory Factor 1 (NRF1) promoter region and increases H4K5ac and H4K8ac levels at the promoter, which increases NRF1 expression and finally promotes colorectal cancer (CRC) cell OXPHOS and CRC progression [136]. In anaplastic large cell lymphoma (ALCL), the STAT3regulated caRNA BlackMamba has the capability to bind and recruit the chromatin remodeling protein lymphoidspecific helicase (LSH/HELLS) to the promoter region of genes related to tumor migration, cytoskeleton formation and inflammation, which increases associated protein expression and maintains the lymphoma kinase-negative (ALK-) ALCL neoplastic phenotype and cell growth [137].…”

LINC00839 in Human Disorders: Insights into its Regulatory Roles and Clinical Impact, with a Special Focus on Cancer

“…This complex, under the guidance of LINC00839, effectively targets the NRF1 promoter, culminating in the acetylation of histones H4 at lysines 5 and 8. Consequently, the expression of NRF1 is enhanced, leading to activation of OXPHOS signaling and mitochondrial metabolism and biogenesis, which collectively drive the progression of CRC 39 .…”

“…For lung cancer 35 and liver cancer 36 , 37 , LINC00839's interactions with miRNAs and proteins offer potential avenues for biomarker discovery and therapeutic interventions. In colorectal cancer 39 , the NRF1-activated OXPHOS pathway, orchestrated by LINC00839, suggests new strategies for targeting tumor metabolism. Moreover, in neuroblastoma 40 , 41 , LINC00839's modulation of NEUROD1 and GLUT1 expression offers insights into potential therapeutic strategies.…”

Association of mitochondrial homeostasis and dynamic balance with malignant biological behaviors of gastrointestinal cancer

“…A total of 522 differential genes were identified by Li et al [ 54 ] through RNA sequencing in HCC cells with OPA1 knock-down and 33 of them had most significant changes in metabolic pathways, suggesting that mitochondrial dysfunction resulted from aberrant fusion might promote HCC cell proliferation by cellular metabolism. Some lncRNAs were found to form complex with NRF1 to activate mitochondrial biogenesis in HCC [ 55 ] and colorectal cancer patients [ 56 ]. NRF1 was also found to activate E2F1 as a transcription factor to promote HCC proliferation by a ChIP-seq analysis for NRF1 target genes [ 57 ].…”