RASSF1A is required for the maintenance of nuclear actin levels

Abstract

Nuclear actin participates in many essential cellular processes including gene transcription, chromatin remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin‐9 and exportin‐6, but how this transport is regulated remains unclear. Here, we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin‐6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumour suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localises to the nuclear envelope (NE) and is required for nucleocytoplasmic actin transport and the concomitant regulation of myocardin‐related transcription factor A (MRTF‐A), a co‐activator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MRTF‐A/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MRTF‐A/SRF in tumour suppression.

RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis—an updated review

“…Moreover, another study suggests the link between RASSF1A and endosomal trafficking through interaction with tumor necrosis factor receptor 1, and states that TNF-R1 internalization is probably dependent on a stable microtubular network influenced by RASSF1A 16 . In addition, a recent report uncovered a new role for endogenous RASSF1A as a regulator of actin nucleocytoplasmic trafficking by corroborating binding of transport receptor exportin-6 to RAN GTPase 89 . Thereby, given the ability of dysregulated vesicle trafficking to promote cancer cell invasion and metastasis 90 , and exosomes to create a pre-metastatic niche 91,92 , their malfunction could contribute to cancer progression of RASSF1A-depleted cells.…”

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

“…Nanaomycin A demethylated the DNA and reactivated the transcription and expression of the gene RASSF1A (ras association domain family 1 isoform A). RASSF1A is a TSG frequently silenced by promoter hypermethylation in cancer [ 101 ]. Kuck et al noted that in lung cancer cells, the promoter region of RASSF1A was sequenced by bisulfite sequence, which confirmed that RASSF1A promoter was highly methylated in A549 cells [ 40 ].…”

Nuclear actin dynamics in gene expression and genome organization

“…A very recent study demonstrated that Ras association domain family isoform 1A (RASSF1A), which is a tumor suppressor frequently silenced in solid cancer supports the binding of Exportin-6 to Ran GTPase, and thus contributes to nucleo-cytoplasmic shuttling of actin. Interestingly, this pathway is aberrant in cancer cells, which results in increased nuclear actin levels and consequently to decreased expression of MRTF-A-SRF target genes [67]. Still another factor regulating MRTF-A/SRF activity is the F-actin binding protein filamin A, which has been shown to interact with MRTF-A, positively regulating SRF activation and thereby postulated to link nuclear actin polymerization to the MRTF-A/SRF transcription complex [68].…”