KCMF1 regulates autophagy and ion channels' function in renal cell carcinoma: a future therapeutic target.

INTRODUCTION: In RCC, systematic procedures such as surgery, chemo-radiation therapy, and application of target-based inhibitors increase the risk of several comorbidities such as chronic kidney disease, hemorrhage, and cardiac arrest that may increase the mortality rate. Even though immune-based checkpoint inhibitor therapies have an overall good response rate, it is restricted to only 30-40% of patients. Hence, an in-depth study of tumor pathophysiology in RCC is needed to identify the new therapeutic target. In RCC, persisted hypoxia is an essential phenomenon for tumor growth and progression. KCMF1 is a newly identified ubiquitin ligase whose domain interacts with destabilized proteins and reprogrammed the ubiquitin coding for lysosome-mediated degradation and autophagy under hypoxic conditions/oxidative stress and maintaining cellular homeostasis. But in RCC, the functional role of KCMF1 remains undefined to date. METHOD: We determined KCMF1 and its associated proteins RAD6 and UBR4 expression and their co-localization using confocal microscopy in tumor and non-tumor tissues samples. Further, immunofluorescence staining was performed to determine autophagy (LC3B, p62), hypoxia-inducible factor (HIF-1A) and ion channel markers (Kv1.3, KCNN4) in RCC patients (n-10). Inductively coupled plasma mass spectrophotometry (ICPMS) was performed to estimate the concentration of potassium (K(+)), sodium (Na(+)) and Zinc (zn(2+)) in tumor and non-tumor cells of RCC patients (n-20). Lastly, images were analyzed using ZEN3.1, and ImageJ software. RESULT AND CONCLUSION: We observed a discrepancy in the formation of ubiquitin ligase, autophagosome via KCMF1, and ionic concentration in tumor cells, which might be one of the possible factors for cancer evolution. KCMF1-associated ubiquitin ligase system could be considered as a novel therapeutic target for RCC in the future.