Kank3, the kidney or KN motif and ankyrin repeat domain-containing protein 3, is part of the Kank family involved in crosstalk between actin and microtubules [2]. It localizes mainly to the plasma membrane in focal adhesions, indirectly regulating the actin cytoskeleton by affecting RhoA and Rac1 [2]. Kank3 was identified as a hypoxia-inducible pro-apoptotic target of p53, and it may be co-opted for vertebrate vascular development [2,6].

In lung adenocarcinoma (LUAD), Kank3 is down-regulated, and its expression significantly impacts patient prognosis [1]. Overexpression of Kank3 inhibits while its silencing enhances the proliferation, invasion, and migration of LUAD cells, regulating these processes through the p38 MAPK pathway [1]. In hepatocellular carcinoma, Kank3 acts as a tumor suppressor controlling cancer cell behavior in an oxygen-dependent manner, as knockdown enhances cell migration and invasion while overexpression inhibits these behaviors [3]. In lung squamous cell carcinoma, pterostilbene exerts anti-cancer function in a Kank3-inhibition-dependent manner [4]. Also, in hypopharyngeal squamous cell carcinoma, Kank3 is down-regulated in lymphatic metastatic tissues compared with adjacent normal tissues and is a favorable prognosis marker [5]. In Piemontese cattle, Kank3 may play a role in arthrogryposis and macroglossia, being involved in processes related to muscular or nervous tissue development, though this needs further validation [7].

In summary, Kank3 has been shown to have tumor-suppressive roles in multiple cancer types, influencing cancer cell proliferation, invasion, and migration. Its functions are often associated with cell-related processes such as actin-microtubule crosstalk, and its down-regulation in certain cancers is linked to poor prognosis. The study of Kank3 provides insights into cancer development mechanisms, potentially offering new therapeutic targets for cancer treatment [1,2,3,4,5].

References:

1. Dai, Ziyu, Xie, Bin, Yang, Baishuang, Hu, Chengping, Chen, Qiong. 2022. KANK3 mediates the p38 MAPK pathway to regulate the proliferation and invasion of lung adenocarcinoma cells. In Tissue & cell, 80, 101974. doi:10.1016/j.tice.2022.101974. https://pubmed.ncbi.nlm.nih.gov/36463587/

2. Tadijan, Ana, Samaržija, Ivana, Humphries, Jonathan D, Humphries, Martin J, Ambriović-Ristov, Andreja. 2020. KANK family proteins in cancer. In The international journal of biochemistry & cell biology, 131, 105903. doi:10.1016/j.biocel.2020.105903. https://pubmed.ncbi.nlm.nih.gov/33309958/

3. Kim, Iljin, Kang, Jengmin, Gee, Heon Yung, Park, Jong-Wan. 2017. A novel HIF1AN substrate KANK3 plays a tumor-suppressive role in hepatocellular carcinoma. In Cell biology international, 42, 303-312. doi:10.1002/cbin.10895. https://pubmed.ncbi.nlm.nih.gov/29047187/

4. He, Hua, Li, Tian. . Pterostilbene exerts anti-lung squamous cell carcinoma function by suppressing the level of KANK3. In Chemical biology & drug design, 104, e14597. doi:10.1111/cbdd.14597. https://pubmed.ncbi.nlm.nih.gov/39044124/

5. Li, Ce, Xu, Chenyang, Guan, Rui, Wei, Dongmin, Lei, Dapeng. 2024. Spatial transcriptomics reveal tumor microenvironment and SLCO2A1 correlated with tumor suppression in hypopharyngeal squamous cell carcinoma. In International immunopharmacology, 142, 113243. doi:10.1016/j.intimp.2024.113243. https://pubmed.ncbi.nlm.nih.gov/39340989/

6. Hensley, Monica R, Cui, Zhibin, Chua, Rhys F M, Leung, Yuk Fai, Zhang, GuangJun. 2016. Evolutionary and developmental analysis reveals KANK genes were co-opted for vertebrate vascular development. In Scientific reports, 6, 27816. doi:10.1038/srep27816. https://pubmed.ncbi.nlm.nih.gov/27292017/

7. Di Stasio, Liliana, Albera, Andrea, Pauciullo, Alfredo, Macciotta, Nicolò P P, Gaspa, Giustino. 2020. Genetics of Arthrogryposis and Macroglossia in Piemontese Cattle Breed. In Animals : an open access journal from MDPI, 10, . doi:10.3390/ani10101732. https://pubmed.ncbi.nlm.nih.gov/32987629/