Tumor suppressor gene VHL is a common essential gene in cancers?

Q&A
1

Hi,

I am confused that tumor suppressor VHL is an common essential gene in many cancers. This means that knockout or inactivation of VHL inhibits cancer cell proliferation, but it is known that knockout or inactivation of VHL promotes cell proliferation. How to explain this?

2

Hi qiaoqinxi,

VHL is an interesting case. It causes loss of viability in most cell lines in DepMap… but not renal clear cell carcinomas, the characteristic cancer most often caused by loss of VHL. This could be because these cells have organically lost VHL before the experiment and already adapted to the loss in some way, or it could be that the kidney cells and a few other types are intrinsically tolerant of VHL loss, and this explains why loss of this gene gives rise to that particular set of tumors. Additionally, from a quick google search: one of the main fitness advantages VHL loss is supposed to provide to tumor cells is upregulation of hypoxia response. This is not something we would expect to see as a growth advantage in our 2D normoxic experiments.

What we can say from DepMap is that most cancer cell lines do not tolerate sudden loss of VHL very well, but renal clear cell carcinomas are a striking exception. It’s possible that losing one copy of VHL at a time, or just culturing the cells longer after VHL knockout, would allow them to recover. It’s also possible that culturing in hypoxia would reveal a fitness advantage for those cells that tolerate its loss.

3

Hi Joshua,

Thanks a lot for your answer.

I agree that cells adapted to the loss of VHL in renal clear cell carcinomas, so these cells can still grow without VHL. Knockout of VHL will give cell a growth advantage in 3D culture or under hypoxia condition.

However, another tumor suppressor, p53, shows totally different results when we compare with VHL. Gene effect of p53 is always higher than 0, which means knockout of p53 will not inhibit cell proliferation or promote cell proliferation (gene effect higher than 0.5). Gene effect of VHL is lower than -0.5 in most cancers except renal clear cell carcinomas, this why VHL is defined as a COMMON ESSENTIAL gene in DepMap. The cells used for Depmap should be cultured under 2D and normxia condition… According to gene effect analysis here, VHL should be an oncogene, not a tumor suppressor that were validated in many studies. I really don’t know how to explain this…

Thanks again for your reply :slight_smile: