KCMF1 Regulates Autophagy and Ion Channels' Function in Renal Cell Carcinoma: a Future Therapeutic Target

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2022 Dec 14

PMID 36515749

Authors

Ashu Singh

Saumitra Dey Choudhury

Prabhjot Singh

Vishwendra Vikram Singh

Som Nath Singh

Alpana Sharma

Affiliations

Soon will be listed here.

Abstract

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) 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.

References

Abraham G, Cherian T, Mahadevan P, Avinash T, George D, Manuel E . Detailed study of survival of patients with renal cell carcinoma in India. Indian J Cancer. 2017; 53(4):572-574. DOI: 10.4103/0019-509X.204758. View

Ashton-Beaucage D, Lemieux C, Udell C, Sahmi M, Rochette S, Therrien M . The Deubiquitinase USP47 Stabilizes MAPK by Counteracting the Function of the N-end Rule ligase POE/UBR4 in Drosophila. PLoS Biol. 2016; 14(8):e1002539. PMC: 4994957. DOI: 10.1371/journal.pbio.1002539. View

Beilke S, Oswald F, Genze F, Wirth T, Adler G, Wagner M . The zinc-finger protein KCMF1 is overexpressed during pancreatic cancer development and downregulation of KCMF1 inhibits pancreatic cancer development in mice. Oncogene. 2010; 29(28):4058-67. DOI: 10.1038/onc.2010.156. View

Capitanio U, Montorsi F . Renal cancer. Lancet. 2015; 387(10021):894-906. DOI: 10.1016/S0140-6736(15)00046-X. View

Corn P . Role of the ubiquitin proteasome system in renal cell carcinoma. BMC Biochem. 2007; 8 Suppl 1:S4. PMC: 2106368. DOI: 10.1186/1471-2091-8-S1-S4. View

Heo A, Kim S, Ji C, Han D, Lee S, Lee S . The N-terminal cysteine is a dual sensor of oxygen and oxidative stress. Proc Natl Acad Sci U S A. 2021; 118(50). PMC: 8685671. DOI: 10.1073/pnas.2107993118. View

Hoffmann E, Lambert I . Ion channels and transporters in the development of drug resistance in cancer cells. Philos Trans R Soc Lond B Biol Sci. 2014; 369(1638):20130109. PMC: 3917363. DOI: 10.1098/rstb.2013.0109. View

Hong J, Kaustov L, Coyaud E, Srikumar T, Wan J, Arrowsmith C . KCMF1 (potassium channel modulatory factor 1) Links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4) and lysosome-mediated degradation. Mol Cell Proteomics. 2015; 14(3):674-85. PMC: 4349986. DOI: 10.1074/mcp.M114.042168. View

Iyer N, Kotch L, Agani F, Leung S, Laughner E, Wenger R . Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998; 12(2):149-62. PMC: 316445. DOI: 10.1101/gad.12.2.149. View

10.

Li Z, Stuart R, Eraly S, Gittes G, Beier D, Nigam S . Debt91, a putative zinc finger protein differentially expressed during epithelial morphogenesis. Biochem Biophys Res Commun. 2003; 306(3):623-8. DOI: 10.1016/s0006-291x(03)00875-1. View

11.

Liu X, Zurlo G, Zhang Q . The Roles of Cullin-2 E3 Ubiquitin Ligase Complex in Cancer. Adv Exp Med Biol. 2020; 1217:173-186. DOI: 10.1007/978-981-15-1025-0_11. View

12.

Mejean A, Ravaud A, Thezenas S, Colas S, Beauval J, Bensalah K . Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2018; 379(5):417-427. DOI: 10.1056/NEJMoa1803675. View

13.

Qu L, Ding J, Chen C, Wu Z, Liu B, Gao Y . Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. Cancer Cell. 2016; 29(5):653-668. DOI: 10.1016/j.ccell.2016.03.004. View

14.

Ross K, Jones R . Immune checkpoint inhibitors in renal cell carcinoma. Clin Sci (Lond). 2017; 131(21):2627-2642. PMC: 5869245. DOI: 10.1042/CS20160894. View

15.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

16.

Swami U, Nussenzveig R, Haaland B, Agarwal N . Revisiting AJCC TNM staging for renal cell carcinoma: quest for improvement. Ann Transl Med. 2019; 7(Suppl 1):S18. PMC: 6462602. DOI: 10.21037/atm.2019.01.50. View

17.

Tan Z, Zhang S, Li M, Wu X, Weng H, Ding Q . Regulation of cell proliferation and migration in gallbladder cancer by zinc finger X-chromosomal protein. Gene. 2013; 528(2):261-6. DOI: 10.1016/j.gene.2013.06.064. View

18.

Vodnala S, Eil R, Kishton R, Sukumar M, Yamamoto T, Ha N . T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science. 2019; 363(6434). PMC: 8194369. DOI: 10.1126/science.aau0135. View

19.

Yip S, Wells C, Moreira R, Wong A, Srinivas S, Beuselinck B . Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Cancer. 2018; 124(18):3677-3683. DOI: 10.1002/cncr.31595. View