p21 and CK2 interaction-mediated HDAC2 phosphorylation modulates KLF4 acetylation to regulate bladder cancer cell proliferation

Abstract

Krüppel-like factor 4 (KLF4) is a transcription factor involved in both tumor suppression and oncogenesis as a transcriptional activator or repressor in a context-dependent manner. KLF4 acts as a regulator of p53 depending on p21 status in breast cancer. However, the mechanisms underlying the distinct role of KLF4 remain poorly understood. Here, we revealed that p21 depletion converted KLF4 from a cell cycle inhibitor to a promoter of bladder cancer cell proliferation. Additionally, KLF4 was acetylated in a p21-dependent manner to inhibit bladder cancer cell growth as a tumor suppressor. However, deacetylated KLF4 functioned as an oncogene promoting bladder cancer cell proliferation. Mechanistically, p21 and CK2 interaction, but not CK2 alone, enhanced HDAC2 phosphorylation and restricted KLF4 deacetylation and subsequent tumor promotion. Furthermore, we observed that KLF4 was acetylated by CBP/p300 and that overexpression of CBP resulted in KLF4 acetylation and tumor suppression even in p21-depleted bladder cancer cells. Moreover, we discovered that Notch-1 knockdown-induced KLF4 is acetylated form of KLF4, which may mediate Notch-1 function in bladder cancer cell proliferation. Our data demonstrate that KLF4 acts as a tumor suppressor or oncogene to activate or repress target gene transcription depending on its acetylation status, which is regulated by p21 and CK2 interaction-mediated HDAC2 phosphorylation. Targeting KLF4 at the post-transcriptional levels may provide novel insight for bladder cancer therapy.

Zebrafish Klf4 maintains the ionocyte progenitor population by regulating epidermal stem cell proliferation and lateral inhibition

“…Mammalian KLF4 suppresses keratinocyte proliferation by transcriptional activation of CDKN1A/p21 expression [35]. Nevertheless, some studies have shown that KLF4 can also facilitate cell proliferation [24, 36, 37]. For example, KLF4 plays an essential role in B cell development and in activation-induced B cell proliferation by regulating Cyclin D2 expression [36].…”

“…For example, KLF4 plays an essential role in B cell development and in activation-induced B cell proliferation by regulating Cyclin D2 expression [36]. KLF4 also functions as an oncogene to promote proliferation of breast cancer and bladder cancer cells in the presence of RAS V12 -Cyclin-D1 signaling or the absence of p21 CIP1 [24, 37]. Altogether, our findings further support the idea that KLF4 may exert distinct functions to regulate stem cell proliferation in a context-dependent manner.…”

Protein kinase CK2: a potential therapeutic target for diverse human diseases

“…Among solid tumors, overexpression and/or important roles have been found for CK2 in glioblastoma, 94 – 98 medulloblastoma, 99 , 100 prostate cancers, 101 – 103 ovarian cancers, 104 – 107 breast cancers, 72 , 108 – 112 head and neck squamous cell cancers, 62 , 113 , 114 lung cancers, 113 , 115 – 117 melanoma, 118 , 119 renal cell carcinoma, 73 , 120 – 122 bladder cancers, 123 , 124 pancreatic cancers, 125 , 126 cholangiocarcinoma, 36 , 127 esophageal cancers, 128 , 129 gastric cancers, 130 – 133 hepatocellular carcinoma, 134 – 137 mesothelioma, 138 cervical cancers, 139 – 141 and other squamous cell carcinoma. 142 In this list, the references quote the first chronological evidence and the most relevant findings of CK2 overexpression or fundamental roles in the indicated type of tumor (not considering the many publications dealing with CK2 inhibitor treatment, unless conclusions highlighted specific CK2 functions in the treated tumor).…”

Krüppel-like factor 4 (KLF4): What we currently know

“…Acetylation of KLF4 at lysine residues 225 and 229 mediated by the p300/CBP complex inhibits the ability of KLF4 to activate downstream targets (18). In urinary bladder cancer cells, p21/CK2 interaction enhances HDAC2 phosphorylation and restricts KLF4 deacetylation and subsequence tumor promotion (19). In contrast, overexpression of p300/CBP causes KLF4 acetylation and switches its activity to a tumor suppressor.…”