Crosstalk between KIF1C and PRKAR1A in left atrial myxoma


Cardiac myxoma (CM) is the most common cardiac tumor. Left atrial myxoma (LAM) is the main subtype of CM seen in clinics. Surgery is the premium treatment, with a good prognosis like an overall survival rate of 96.8% 10 years after surgery1. The postoperative recurrence rate of sporadic CM is only 1%, whereas the postoperative recurrence rate of familial patients is as high as 20%2,3. There’s only one pathogenic gene recognized: Protein Kinase cAMP-Dependent Type I Regulatory Subunit Alpha (PRKAR1A). Inactivation of PRKAR1A is related to the Carney complex (CNC), a rare multiple endocrine tumor syndrome characterized by pigmentary abnormalities of the skin and mucous membranes with tumors such as cardiac myxoma, ductal adenomas of the breast, testicular tumors, and thyroid tumors, accompanied by Primary Pigmented Nodular Adrenocortical Disease (PPNAD)4. It has been found that 90% of CM is sporadic and less than 10% is familial in the context of CNC due to germline inactivation variants in the PRKAR1A gene5. 70% of familial CNCs carry germline inactivating variants of PRKAR1A; only 37% of sporadic CNCs carry PRKAR1A variants; and PRKAR1A variants are usually not found in sporadic CM, especially LAM5,6. These all suggest that more pathogenic genes or pathways are undiscovered.


This study first collected D1 and D2 patients without PRKAR1A variants, performed WES on myxoma tumor tissues from patients D1, D2, and PBMCs from D2, and performed RNA-seq on myxoma tumor tissues from patients D1 and D2. Based on the variant list for each sample, we performed an initial screening by variant location, function, and frequency in the population. The disease was then analyzed in two steps according to the hypothesis that it was caused by a hereditary variant or a somatic variant, then systematic errors were excluded, and finally the common variants were filtered out according to our own laboratory heart variation data. Unfortunately, we did not find candidate loci for somatic variants that cause disease, but we did find candidate loci for hereditary variants that cause disease. After Sanger sequencing and qRT-PCR validation, we identified a new candidate pathogenic gene, KIF1C. In our study, we found that there is a close relationship between the expression of KIF1C and PRKAR1A; e.g., the expression of KIF1C is reduced in tissues and cells with KIF1C variants, and the expression of PRKAR1A is reduced too at the same time. Thus, we speculated that KIF1C could regulate the expression of PRKAR1A. Polymorphisms in KIF1C showed their transcriptional regulatory role in a mouse study of experimental autoimmune orchitis7. As expected, KIF1C was shown to be expressed in the nucleus and bound to the promoter of PRKAR1A to regulate its transcriptional activity, thus regulating the expression of PRKAR1A. PRKAR1A is known to encode the alpha regulatory subunit of PKA kinase. Thus, we focused on the role of the PKA pathway in the pathogenesis of LAM. Pathway studies showed that knockdown of KIF1C expression decreased PRKAR1A expression, increased cAMP-dependent PKA activity, increased ERK1/2 phosphorylation, decreased CDH1 expression, and promoted epithelial-to-mesenchymal transition (EMT), which promoted tumorigenesis; at the same time, increased PKA activity, increased SRC phosphorylation, increased STAT3 phosphorylation, decreased downstream TP53 expression, inhibited the expression of the proliferation-inhibiting gene CDKN1A, and inhibited the expression of the pro-apoptotic gene BAX, which promotes cell proliferation and inhibits apoptosis and leads to tumorigenesis. In addition, the inhibition of KIF1C expression reduced SRC expression, and the inhibition of SRC in turn reduced KIF1C expression, suggesting that KIF1C and PRKAR1A can form a positive feedback regulation through the above signaling pathway and promote tumorigenesis.


KIF1C is a member of the kinesin family of proteins (KIFs). KIFs are not only involved in intracellular transport, but also in the regulation of podosomes during cell migration8,9. Previously reported variants of KIF1C were associated with Hereditary Spastic Paraplegia (HSP), especially the SPG58 type10. Variants of KIF1C may lead to insufficient or blocked transport of α5β1 integrins, reduce the regeneration of peripheral neurons that have been injured by SPG58-related causative factors, and lead to various neurodevelopmental defects11. The development of the nervous system begins in the embryonic ectoderm, where the Neural Crest Cells (NCCs) also originate. NCCs are a group of stem cells with strong migratory properties and extensive differentiation potential during embryonic development12. Some NCCs can migrate into the cardiac outflow tract via the ventral pathway and participate in the development of the heart; these are called cardiac neural crest cells (CNCCs). In humans as well as in animal models, developmental defects of CNCCs will affect the formation of the cardiac outflow tract, the great vessels, and the atrial and ventricular septum, leading to the development of congenital heart disease13,14. The origin of CM is not clear; it may originate from a population of mesenchymal cardiomyocyte progenitors with both neural and endothelial differentiation capabilities15. It has also been suggested that CM is derived from neuroendocrine tissues based on pattern analysis of neuroendocrine markers16. It has also been suggested that CM is a single-tissue-like benign embryonic endocardial endothelioma17. Thus, it is also interesting to see whether KIF1C is involved in CM development by affecting the migration of CNCCs during embryonic development.


Most KIFs are usually highly expressed in tumors and associated with poor prognosis, and there are ongoing studies of KIF inhibitors for tumor therapy18. However, KIF1C and the UNC104 subfamily consisting of KIF1A, KIF1B, and KIF1C, which are the closest of its relatives, have all shown tumor-suppressive effects19. This may be related to their same FHA domain. Many proteins containing FHA domains, such as AGGF1, CHK2, and MDC1, exert tumor-suppressive effects by transcriptionally regulating the expression of genes associated with DNA damage repair, cell growth, and cell cycle checkpoints20-22. However, whether the FHA domain also confers a transcriptional regulatory function on KIF1C has not been thoroughly investigated. In addition, the transcriptional regulatory mechanism of KIF1C is not clear, and whether it participates in the transcriptional process as a cofactor for transporting transcription factors needs to be further investigated.


Figure. Inhibition of KIF1C activated downstream pathways of PKA.

Schematic diagram for the tumorigenesis mechanisms of the inhibition of KIF1C mediated by PRKAR1A.





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