UHMK1 aids colorectal cancer cell proliferation and chemoresistance through augmenting IL-6/STAT3 signaling

Abstract

UHMK1, a serine/threonine kinase with a U2AF homology motif, is implicated in RNA processing and protein phosphorylation. Increasing evidence has indicated its involvement in tumorigenesis. However, it remains to be elucidated whether UHMK1 plays a role in the development of colorectal cancer (CRC). Here, we demonstrated that UHMK1 was frequently upregulated in CRC samples compared with adjacent normal tissue and high expression of UHMK1 predicted poor outcomes. Knockdown of UHMK1 by siRNAs restrained CRC cell proliferation and increased oxaliplatin sensitivity, whereas overexpression of UHMK1 promoted CRC cell growth and oxaliplatin resistance, suggesting that UHMK1 plays important oncogenic roles in CRC. Mechanistically, we showed that UHMK1 had a significant effect on IL6/STAT3 signaling by interacting with STAT3. The interaction of UHMK1 with STAT3 enhanced STAT3 activity in regulating gene transcription. Furthermore, we found that STAT3 could in turn transcriptionally activate UHMK1 expression in CRC cells. The complementary experiments for cell growth and oxaliplatin resistance indicated the interdependent relationship between UHMK1 and STAT3. Thus, these collective findings uncovered a new UHMK1/STAT3 positive feedback regulatory loop contributing to CRC development and chemoresistance.

UHMK1 promotes lung adenocarcinoma oncogenesis by regulating the PI3K/AKT/mTOR signaling pathway

“…UHMK1 has been implicated as an attractive therapeutic target by exerting its potent oncogenic functions in different ways in many types of cancer. 20 , 21 , 22 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 40 This motivated us to explore the role and possible mechanism of action of UHMK1 in LUAD. In our study, we identified UHMK1 as significantly overexpressed in LUAD patients, leading to a poor prognosis.…”

“… 41 , 42 , 43 Under certain conditions, autophagy contributes to cell survival and improves the tolerance to drug therapy. 44 , 45 Interestingly, some studies have indicated that UHMK1 can mediate oxaliplatin, 28 5‐fluorouracil 46 resistance in colorectal cancer, and vemurafenib resistance in melanoma. 22 Our findings might provide insights into UHMK1‐mediated drug resistance in tumors.…”

“…Being the only identified kinase with the U2AF homology motif, UHMK1 is equipped with both the functions of phosphorylation and mRNA splicing. UHMK1 has been implicated as an attractive therapeutic target by exerting its potent oncogenic functions in different ways in many types of cancer 20–23,25–32,40 . This motivated us to explore the role and possible mechanism of action of UHMK1 in LUAD.…”

“…The aberrant UHMK1 expression is always accompanied by changes in cancer‐related pathways, like the mitogen‐activated protein kinases (MAPK)/extracellular‐signal‐regulated‐kinase (ERK) and Hippo/yes‐associated protein 1 (YAP) signaling pathways in liver cancers, 25,26 and the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in colorectal cancers 28 . KEGG pathway analysis of our transcriptome data revealed that altered UHMK1 expression significantly affected the PI3K/AKT signaling pathway.…”

“…Research on UHMK1 was initially focused on neurological diseases such as schizophrenia 17 , 18 because of its abundant expression in the nervous system. 19 In the last few years, many researches have revealed the function of UHMK1 in promoting the initiation and progression of different types of cancer, including ovarian cancer, 20 , 21 melanoma, 22 , 23 cervical cancer, 24 liver cancer, 25 , 26 colorectal carcinoma, 27 , 28 pancreatic cancer, 29 , 30 , 31 and gastric cancer. 32 However, no studies have investigated the function and regulatory mechanism of UHMK1 in LUAD.…”